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Chris Eugene Brough
2015
The Dissertation Committee for Chris Eugene Brough Certifies that this is the
approved version of the following dissertation:
Novel Uses of Pharmaceutical Polymers as enabled by KinetiSol®
Dispersing
Committee:
Robert O. Williams III, Supervisor
James W. McGinity
Christopher R. Frei
Sean M. Kerwin
Dave A. Miller
Novel Uses of Pharmaceutical Polymers as enabled by KinetiSol®
Dispersing
by
Chris Eugene Brough, B.S., M.S., M.B.A.
Dissertation
Presented to the Faculty of the Graduate School of
The University of Texas at Austin
in Partial Fulfillment
of the Requirements
for the Degree of
Doctor of Philosophy
The University of Texas at Austin
August, 2015
Dedication
To my wife, Jessica, who has been a huge support in all of my business and scholastic
adventures.
To my three kids, Ezra, Scarlett & Levi, who have been patient with their dad as he has
had some late nights and early mornings.
To my father, who always wanted one of his boys to become a ‘doctor’.
v
Acknowledgements
I would like to thank my boss, Gershon Yaniv, for pushing me to pursue this Ph.D.
and for also allowing me to be employed full-time to allow it to happen. I would like to
thank Robert O. Williams III for being such a wonderful supervisor and allowing me the
flexibility to juggle school and work. I could not have completed the program without his
patience, understanding, support and guidance. James W. McGinity’s support of the
technology has not only helped DisperSol get its start, but also sparked interest within me
for this particular field of study, of which I am very grateful.
I would like to thank the faculty and the members on my committee. I cannot take
the time here to write all of the things I learned nor the ways I was influenced, but I am
very grateful for them. This may sound cheesy, but I really felt that every one of them
genuinely cared about my success. In the vigor of this program, it was nice to feel that
everyone was on my side.
I need to specifically thank Dave Miller, Justin Keen and Justin Hughey. As I think
about the hours that these men spent with me, I am humbled by their generosity, knowledge
and kindness. I could not have done this without them. Also, as funny as this sounds, I
want to thank Texas. I know I would not have ever gotten involved in this industry, if my
company wasn’t bought and moved to Texas.
There is no way that I can adequately thank my wife, Jessica. She has had to handle
most parental duties without me. I know that being a ‘single mother’ to our three kids has
been a real challenge at times, but she has been amazing. She is SuperMom and SuperWife,
but the world will never know it. I just want her to know that I do.
vi
Finally, I would like to thank my Father in Heaven. As I was contemplating getting
this Ph.D. (rather as Gershon was pushing me to do it), I really didn’t want to because I felt
that my two master’s degrees were more than sufficient for what I wanted to do in life. As
I made it a matter of prayer, it was clear to me that this was something that God wanted me
to do. I could not count the times that I wanted to quit or the times that I felt bad as I saw
how this program was negatively effecting my wife and kids. But, each time I turned to
Him, I received comfort and strength. I honestly still don’t know why I did this. If I knew
how hard it was going to be, I probably wouldn’t have done it. But, I have faith that there
is a reason. At the end of the day, I just want to be His servant and to make the world a
little better place. I just hope that the sacrifice this bundle of paper represents actually
results in the outcome that He wanted.
vii
Novel Uses of Pharmaceutical Polymers as enabled by KinetiSol®
Dispersing
Chris Eugene Brough, Ph.D.
The University of Texas at Austin, 2015
Supervisor: Robert O. Williams III
Poor water-solubility is a common characteristic of drug candidates in
pharmaceutical development pipelines today. Various processes have been developed to
increase the solubility, dissolution rate and bioavailability of these active ingredients
belonging to BCSII and IV classifications. Over the last decade, nano-crystal delivery
forms and amorphous solid dispersions have become well established in commercially
available products and industry literature. Chapter 1 is a comparative analysis of these two
methodologies primarily for orally delivered medicaments. The thermodynamic and
kinetic theories relative to these technologies are presented along with a survey of
commercial relevant scientific literature. Marketed products from both technologies are
presented, but there appears to be more amorphous dispersion products on the U.S. market
today and current development trends are showing an industry preference for amorphous
solid dispersions.
Many pharmaceutical polymers have been investigated as the primary component
in amorphous solid dispersions for their ability to increase the apparent water solubility of
poorly water-soluble drugs. Polyvinyl alcohol (PVAL) has not been investigated as a
concentration enhancing polymer owing to its high melting point/high viscosity and poor
organic solubility. Due to the unique attributes of the KinetiSol® Dispersing (KSD)
viii
technology, PVAL has been enabled for this application and Chapter 2 contains an initial
investigation into various grades for improvement of the solubility and bioavailability of
the poorly water-soluble model drug, itraconazole (ITZ). Polymer grades were chosen with
variation in molecular weight and degree of hydroxylation to determine the effects on
performance. Differential scanning calorimetry, powder x-ray diffraction, polarized light
microscopy, size exclusion chromatography and dissolution testing were used to
characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also
conducted to compare the selected formulation to current market formulations of ITZ.
Chapter 3 continues the investigation into the use of PVAL as a concentration
enhancing polymer for amorphous solid dispersion. The previous chapter revealed that the
88% hydrolyzed grade was optimal for ITZ compositions with regard to solid-state
properties, non-sink dissolution performance and bioavailability enhancement. This
chapter explores the influence of molecular weight for the 88% hydrolyzed grade in the
range of 4 to 8 mPa·s with the top performing grade from both chapters emerging as PVAL
4-88. Amorphous dispersions at 10, 20, 30, 40 and 50% ITZ drug loads in PVAL 4-88
were compared by dissolution performance. Analytical tools of diffusion-ordered
spectroscopy and Fourier transform infrared spectroscopy were employed to understand
the interaction between drug and polymer. Finally, results from a 30 month stability test
of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous
dispersions can be achieved.
The KinetiSol® Dispersing (KSD) technology has been shown to create solid
dispersion systems from challenging drugs and highly viscous polymers. The focus has
been primarily using this technology for solubility enhancement, but it can be advantageous
for other obstacles facing the pharmaceutical development industry. Chapter 4 contains an
investigation into the use of the technology for producing abuse deterrent formulations for
ix
the drug, theophylline, which is used as a model for oxycodone. Various high molecular
weight polymers are combined with plasticizers to produce mechanical and chemical
properties sufficient to resist alcohol dose dumping, size reduction for immediate release
and syringeability for injection. Thus, the KinetiSol® Dispersing (KSD) technology can be
used as a formulation platform for creating abuse deterrent delivery forms in addition to
solid amorphous dispersions for solubility enhancement.
x
Table of Contents
List of Tables ...................................................................................................... xiii
List of Figures ..................................................................................................... xiv
List of Equations ................................................................................................ xvi
Chapter 1: Amorphous Solid Dispersions and Nano-crystal Technologies for
Poorly Water-Soluble Drug Delivery ........................................................17
1.1 INTRODUCTION.........................................................................................17
1.2 SCIENTIFIC FOUNDATION .........................................................................18
1.2.1 Nano-crystal Delivery Forms ......................................................19
1.2.2 Amorphous Dispersions ..............................................................22
1.3 PROCESSES ...............................................................................................26
1.3.1 Nano-crystal Technologies .........................................................26
1.3.2 Amorphous Dispersion Technologies .........................................27
1.4 RESEARCH COMPARISONS ........................................................................30
1.5 MARKETED PRODUCTS .............................................................................36
1.5.1 Nano-crystal Products .................................................................36
1.5.2 Amorphous Dispersion Products ................................................38
1.6 CONCLUSION ............................................................................................44
Chapter 2: New Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for
Poorly Water-soluble Drug Delivery (Part 1) ..........................................45
2.1 Introduction .............................................................................................45
2.2 Materials .................................................................................................51
2.3 Methods...................................................................................................51
2.3.1 KinetiSol® Dispersing (KSD) .....................................................51
2.3.2 Differential Scanning Calorimetry (DSC) ..................................51
2.3.3 Powder X-Ray Diffraction (XRD) ..............................................52
2.3.4 Polarized Light Microscopy (PLM) ............................................52
2.3.5 Size Exclusion Chromatography (SEC)......................................52
2.3.6 Non-sink Dissolution Analysis ...................................................53
xi
2.3.7 High Performance Liquid Chromatography ...............................53
2.3.8 In Vivo Studies ............................................................................53
2.4 Results and Discussion ...........................................................................55
2.4.1 Preliminary Evaluation of PVAL Molecular Weight .................55
2.4.2 Solid-state Analysis ....................................................................57
2.4.3 Non-sink, Gastric Transfer Dissolution Analysis .......................65
2.4.4 In Vivo Study...............................................................................67
2.5 Conclusion ..............................................................................................70
Chapter 3: New Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for
Poorly Water-soluble Drug Delivery (Part 2) ..........................................71
3.1 Introduction .............................................................................................71
3.2 Materials .................................................................................................74
3.3 Methods...................................................................................................74
3.3.1 KinetiSol® Dispersing (KSD) .....................................................74
3.3.2 Powder X-Ray Diffraction (XRD) ..............................................74
3.3.3 Polarized Light Microscopy (PLM) ............................................75
3.3.4 High Performance Liquid Chromatography (HPLC) .................75
3.3.5 Non-Sink Dissolution Analysis...................................................75
3.3.6 Precipitation Inhibition Analysis ................................................76
3.3.7 Fourier Transform Infrared Spectroscopy (FTIR) ......................76
3.3.8 Diffusion-Ordered Spectroscopy (DOSY) ..................................77
3.4 Results and Discussion ...........................................................................78
3.4.1 Evaluation of PVAL Molecular Weight .....................................78
3.4.2 Drug Loading Evaluation ............................................................80
3.4.3 Evaluation of the ITZ/PVAL Interaction ....................................83
3.4.4 Evaluation of Stability ................................................................88
3.5 Conclusion ..............................................................................................92
Chapter 4: Novel formulation approach for multiparticulate abuse deterrent
development .................................................................................................93
4.1 Introduction .............................................................................................93
xii
4.2 Materials .................................................................................................99
4.3 Methods...................................................................................................99
4.3.1 KinetiSol® Dispersing (KSD) .....................................................99
4.3.2 Non-Sink Dissolution Analysis.................................................100
4.3.3 Dart Impact Test .......................................................................100
4.3.4 Coffee Grinder Size Reduction Test .........................................100
4.3.5 Syringeability Test ....................................................................101
4.3.6 Water Extraction Test ...............................................................101
4.4 Results and Discussion .........................................................................102
4.4.1 Formulation Development ........................................................102
4.4.2 Abuse Testing ...........................................................................105
4.5 Conclusion ............................................................................................113
Bibliography .......................................................................................................114
Vita .....................................................................................................................134
xiii
List of Tables
Table 1.1: Examples of commercial nano crystal products [58] ........................36
Table 1.2: Examples of current amorphous dispersion products [81] (modified).
...........................................................................................................38
Table 2.1: Properties of PVAL (EMD Millipore) [109] ....................................47
Table 2.2: Rat PK study design ..........................................................................54
Table 2.3: Rat PK mean calculations .................................................................69
Table 4.1: Categories for abuse deterrence as defined by the U.S. FDA. ..........94
Table 4.2: Formulations tested to determine excipient trends (n=1). ..............103
xiv
List of Figures
Figure 1.1: Three basic quantities that determine solubility of solid solute. .......22
Figure 1.2: ‘Spring & Parachute’ concept for supersaturation stability [43]
(adapted). ..........................................................................................24
Figure 1.3: Dose proportionality of compound 3 in 10% Tween (-▲-) as the
crystalline form; in 0.5% Methocel/0.24% SLS as the amorphous form (-
■-) and in solid dispersion at 50% drug loading in HPMC-AS given as
suspension in Methocel (-●-) from 10 mpk to 750 mpk dosed at 5 ml/kg
in Sprague Dawley rats (n=4) [74] (corrected). ................................33
Figure 1.4: Timeline of FDA approved amorphous dispersion and nano-crystal
products. ............................................................................................42
Figure 2.1: SEC profiles of unprocessed powders and processed compositions.56
Figure 2.2: XRD profiles of PVAL grades used in study....................................58
Figure 2.3: XRD profiles of ITZ and KSD compositions ...................................58
Figure 2.4: Nonreversing Heat Flow DSC thermograms for 4 mPa·s grades of PVAL
...........................................................................................................60
Figure 2.5: Reversing Heat Flow DSC thermograms for 4 mPa·s grades of PVAL
...........................................................................................................60
Figure 2.6: Nonreversing Heat Flow DSC thermograms for KSD compositions and
ITZ ....................................................................................................61
Figure 2.7: Reversing Heat Flow DSC thermograms for KSD compositions and ITZ
...........................................................................................................62
Figure 2.8: Dissolution Profiles for 4 mPa·s grades KSD compositions.............66
xv
Figure 2.9: Dissolution Profiles for 4 mPa·s grades KSD compositions presented as
concentration (C) relative to the saturation concentration (Cs) of ITZ at
the respective pH...............................................................................66
Figure 2.10: Rat PK of PVAL 4-88 compositions compared with Onmel™. .......68
Figure 3.1: Dissolution profiles of 20% ITZ in PVAL 4-, 5-, 8- and 18-88. ......78
Figure 3.2: Precipitation inhibition curves of 20% ITZ in PVAL 4-88, 5-88, 8-88
and 18-88. .........................................................................................79
Figure 3.3: Dissolution comparison of different ITZ loadings in PVAL 4-88. ...81
Figure 3.4: FTIR-ATR spectra of amorphous ITZ, PVAL 4-88, and amorphous
dispersions.........................................................................................84
Figure 3.5: DOSY maps of (A) PVAL 4-88 and (B) 20% ITZ in PVAL 4-88
amorphous dispersion. ......................................................................86
Figure 3.6: XRD profiles of ITZ, initial and 30 month old amorphous dispersions.
...........................................................................................................89
Figure 3.7: pH change dissolution comparing initial and 30 month ambient storage
amorphous dispersions of ITZ:PVAL 4-88 (30% drug loading). .....90
Figure 4.1: Dissolution profiles of lead formulation in 0.1 N HCl and 40% Ethanol
(n=3). ...............................................................................................105
Figure 4.2: Post Coffee Grinder Test Particle Size distribution. .......................106
Figure 4.3: Dissolution Profile of Original Size and Coffee Ground Material (n=3).
.........................................................................................................107
Figure 4.4: Mortar and Pestle approach for size reduction of multiparticulates.108
Figure 4.5: Result of Syringeability test of lead formulation. ...........................109
Figure 4.6: Dissolution Profiles from the Water Extraction Test. .....................111
xvi
List of Equations
Equation 1.1: Maximum absorbable dose (MAD) formula...............................18
Equation 1.2: The Nernst-Brunner equation. ....................................................19
Equation 1.3: Ostwald-Freundlich equation. .....................................................20
Equation 1.4: Kelvin equation. ..........................................................................21
Equation 1.5: Three basic quantities governing solubility. ...............................22
17
Chapter 1
Amorphous Solid Dispersions and Nano-crystal Technologies for Poorly
Water-Soluble Drug Delivery [1]
[1] Previously published: Brough, C. and R.O. Williams III, Amorphous solid
dispersions and nano-crystal technologies for poorly water-soluble drug delivery.
International Journal of Pharmaceutics, 2013. 453(1): p. 157-166.
Research and writing was supervised by Robert O. Williams III.
1.1 INTRODUCTION
Poorly-water soluble drug substances are a significant percentage of the molecular
entities in the industry’s drug development pipeline and are a growing percentage of those
commercially available [2-4]. In the past, the industry consensus was to view these as
highly risky development candidates [5]. However, given their prevalence, industry
consensus has shifted from an attitude of avoidance to one of acceptance as increasing
research dedication is given to solving solubility challenges [6]. Whether the increase in
number of poorly water-soluble entities is due to modern high-through put screening
methodologies [7] or credited to development on increasingly biocomplex diseases
requiring higher lipophilicity and larger molecular weight, the challenge of poor solubility
is not disappearing in the foreseeable future [8, 9].
Addressing this issue, the pharmaceutical industry has developed multiple methods
for increasing the apparent solubility of crystalline drugs. Traditionally, salt formation was
preferred by medicinal and synthetic chemists for weak bases or weak acids [10].
Unfortunately, only 20-30% of new molecules form salts easily, so 70-80% of those entities
must find another route to improved solubility [11]. Cyclodextrins [12], self-emulsifying
drug delivery systems (SEDDS)[13], solid lipid nanoparticles [14], liposomes [15],
micelles [16], soft gelatin capsules [17], co-crystals [18], pH micro-environmental
18
modifiers [19], and high energy polymorphs [20] are some of the routes available to
pharmaceutical scientists. However, the last decade has shown the prevalence of two
solubility/dissolution rate improvement methods both in scientific literature and marketed
products: nano-crystal delivery forms and solid amorphous dispersions.
1.2 SCIENTIFIC FOUNDATION
Solubility of the drug substances plays a significant role in its bioavailability. The
Biopharmaceutical classification system (BCS) was established in order to classify
intestinal absorption [21]. Poorly water-soluble compounds are grouped into BCS Class II
(high permeability, low solubility) or BCS Class IV (low permeability, low solubility)
depending upon their permeability categorization [22].
There are multiple complex factors in drug absorption, but a straightforward
conceptual approach to understanding solubility’s role can be expressed by the maximum
absorbable dose (MAD) formula:
MAD = 𝐾𝑎 ∙ 𝑆𝑝𝐻 ∙ 𝑉𝑆𝐼 ∙ 𝑡
Equation 1.1: Maximum absorbable dose (MAD) formula.
Where Ka is the intestinal absorption rate constant (related to permeability), SpH is
the solubility at intestinal pH, VSI is the volume of fluid in the small intestine available for
drug dissolution and t is the transit time through the small intestine [23, 24]. While this is
a more simplistic model, it does illustrate important points in the challenge of poorly
soluble drug absorption. First, the solubility at the site of absorption is critical after the pH
transition from the acidic gastric environment [25]. Delivery forms must either include
dissolution in the gastric environment and maintenance of solubility through the pH
transition into the intestines or acceptably rapid dissolution rates at intestinal pH to achieve
19
solubility during the intestinal transit time. Second, Ka, the intestinal absorption rate, must
also be considered with increased solubility. At low solubility, the SpH is likely the limiting
factor in the maximum absorbable dose. If the drug solubility is increased substantially,
the limiting factor can shift from solubility to the intestinal absorption rate [26]. Thus, it
may be more important to stabilize drug solubility for the entire intestinal transit time rather
than to maximize solubility for a portion of it.
1.2.1 Nano-crystal Delivery Forms
Both nano-crystal delivery forms and solid amorphous dispersions increase the
amount of drug dissolved at the site of absorption, but they achieve this by different
mechanisms. Nano-crystal delivery relies on reduced particle size for increased solubility
and dissolution rate [27]. The Nernst-Brunner equation (Noyes-Whitney equation
modified with Fick’s second law) illustrates the effect of smaller particle size on dissolution
as seen in Equation 1.2:
𝑑𝐶
𝑑𝑡=
𝐷𝑆
𝑉ℎ(𝐶𝑠 − 𝐶)
Equation 1.2: The Nernst-Brunner equation.
Where dC/dt is the change of concentration over time (dissolution), D is the
diffusion coefficient, S is the surface area, V is the volume of the dissolution medium, h is
the thickness of the diffusion layer, CS is the saturation solubility and C is the instantaneous
concentration at time t [28]. As particles are reduced in size the surface area increases; as
particles are reduced to the nano scale the surface area increases dramatically. In addition
to affecting surface area, with particle sizes less than about 50µm the thickness of the
diffusion layer appears to decreases as well [29]. Thus, nano sizing increases dissolution
20
by simultaneously increasing surface area in the numerator and decreasing the diffusion
layer thickness in the denominator of Equation 1.2.
The relationship of solubility of a small particle in a bulk solution is given by the
Ostwald-Freundlich equation (Equation 1.3), which is analogous to the Gibbs-Kelvin
equation [30].
ln (𝑥𝑅
𝑥∞) =
2σαγυ2γ
𝑘𝐵𝑅𝑇
Equation 1.3: Ostwald-Freundlich equation.
Where the solubility, xR, of a small solid particle (phase γ) in the ideal bulk solution
(phase α) is related to radius, R. The other variables are as follows: x∞ is the relative
concentration of solute in phase α, σαγ is the surface tension of the solid particle at its
boundary with phase α, υ2γ is the volume per molecule in the solid particle, kB is the
Boltzmann constant and T is the temperature. According to the equation, particles with a
very small radius will have increased solubility. This indicates that nanoparticles not only
affect surface area, S, and the diffusion layer thickness, h, in the Nernst-Brunner equation,
but also the saturation solubility, CS. Entering values to simulate a drug in intestinal fluid
(assuming a drug molecular weight of 500 and an σαγ value of 15-20 mN m-1 for the crystal-
intestinal fluid surface tension) Equation 1.3 predicts an approximate 10-15% increase in
solubility for a particle size of 100 nm [31].
Further illustrations of increased solubility of small particles have been reported
[32, 33]. Junghanns et al. used an equation related to the Ostwald-Freundlich equation, the
Kelvin equation, which describes the relationship between the radius of a liquid droplet
and the vapor pressure leading to evaporation. Equation 1.4 is the Kelvin equation.
21
ln (𝑝
𝑝o) =
2γ𝑉𝑚
Ȓ𝑅𝑇
Equation 1.4: Kelvin equation.
Where p is the vapor pressure, po is the saturated vapor pressure, γ is the surface
tension, Vm is the molar volume, Ȓ is the universal gas constant, R is the radius of the droplet
and T is the temperature. Under the assumption that a transfer of molecules from a liquid
phase to a gas phase is in principal identical to the transfer of molecules from a solid phase
to a liquid phase, the properties of BaSO4 were entered into the Equation 1.4. Using the
curvature of the nanoparticle surfaces to estimate pressures, the Kelvin equation shows an
increase in saturation solubility for particles smaller than 1 µm.
Nanoparticles are much more unstable than microparticles because of the extra
Gibbs free energy contribution related to reducing particle size and primarily due to surface
energy [34]. Addressing this extra contribution is key to formulating pharmaceutical
nanoparticles because they will tend to agglomerate to minimize their total energy [35].
Approaches to stabilizing drug nanoparticles can be categorized into two groups:
thermodynamic stabilization which uses surfactants or block copolymers for particle
stability or kinetic stabilization which uses energy input to compensate for Gibbs free
energy [34]. For maximum effectiveness, the two approaches are often combined [36].
Careful selection of the amount of stabilizer is as important as the selection of the type of
stabilizer. For example, one obstacle to stabilization is Ostwald ripening, which is the
phenomenon in which smaller particles in solution dissolve and deposit on larger particles
in order to reach a more thermodynamically stable state by minimizing the surface to area
22
ratio [37]. Too little stabilizer allows agglomeration of nanoparticles and too much
stabilizer promotes Ostwald ripening [38].
1.2.2 Amorphous Dispersions
Understanding the benefit of solid amorphous dispersions must be explained in
terms of enthalpic energy. There are three basic quantities governing the solubility (S) of
a given solid solute [8]:
𝑆 = 𝑓(𝐶𝑟𝑦𝑠𝑡𝑎𝑙 𝑃𝑎𝑐𝑘𝑖𝑛𝑔 𝐸𝑛𝑒𝑟𝑔𝑦 + 𝐶𝑎𝑣𝑖𝑡𝑎𝑡𝑖𝑜𝑛 𝐸𝑛𝑒𝑟𝑔𝑦 + 𝑆𝑜𝑙𝑣𝑎𝑡𝑖𝑜𝑛 𝐸𝑛𝑒𝑟𝑔𝑦)
Equation 1.5: Three basic quantities governing solubility.
The crystal packing energy term accounts for the energy necessary to disrupt the
crystal lattice and remove isolated molecules. The cavitation energy term accounts for the
energy required to disrupt water in order to create a cavity in which to host the solute
molecule. The solvation energy term accounts for the release of energy as favorable
interactions are formed between the solvent and solute. A graphical representation is
shown in Figure 1.1.
Figure 1.1: Three basic quantities that determine solubility of solid solute.
23
In relative terms, the crystal packing energy is larger than both cavitation and
solvation energies and thus, the driving force behind solubility. The intent in formulating
an amorphous solid dispersion is to minimize this energy component by disrupting the drug
crystal lattice in the delivery form. In conjunction with solubility enhancing polymeric
carriers, the apparent solubility can be increased by up to 10,000 fold or more [39-42]. In
terms of the Nernst-Brunner equation, drastic increases of the saturation solubility, CS,
result in a much faster dissolution rate.
Solid amorphous dispersions essentially contain stored potential energy that can
‘spring’ the molecular entity into a supersaturated state [43, 44]. Since supersaturation is
thermodynamically unstable, the formulation must also provide a ‘parachute’ to keep the
solubility from rapidly returning to the crystalline drug equilibrium solubility (Figure 1.2)
to maintain elevated drug concentrations for the duration of intestinal transit to achieve the
maximum absorbable dose. In general, solubility enhancing polymers are reported to
function well as a parachute or stabilizer due to drug-polymer interactions in solution and
by adsorption of the polymer on the growing crystal [45]. Other solubility enhancing
formulations may require additional excipients to function as the parachute to retard the
descent from high to low energy forms of the drug. Examples of polymers that have been
investigated for their stabilizing effect are PVP [46], PEG [47], methylcellulose (MC) [48]
and HPMC [49].
24
Figure 1.2: ‘Spring & Parachute’ concept for supersaturation stability [44] (adapted).
A concern with solid dispersions is the possibility of the amorphous drug substance
undergoing crystallization on storage. The effect of moisture on storage stability is an
another concern because the presence of water may increase drug mobility and promote
drug crystallization [50]. Additionally, some polymers used in solid dispersions are
hygroscopic, which may result in phase separation, crystal growth or conversion from a
metastable crystalline form to a more stable crystalline structure during storage [51]. This
would result in continually decreasing the solubility and dissolution rate as well as lower
the in vivo performance during the product’s shelf-life.
The above challenges can be mitigated by proper polymer selection, drug loading
optimization and appropriate product packaging selection. Amorphous solid dispersions
can be rendered physically stable via kinetic stabilization: i.e., freezing the amorphous drug
substance in the polymer matrix to restrict molecular mobility to prevent nucleation and
crystal growth. It has been reported that for adequate kinetic stability, the Tg of the
composite matrix should be 50 °C above the maximum storage temperature [52]. From
this perspective, polymer selection is important to ensure a high composite Tg for the
25
preservation of the amorphous drug. A polymer may also stabilize an amorphous drug
substance via drug-polymer intermolecular interactions such as hydrogen bonding, Van der
Waals forces, etc. Such interactions can be estimated a priori utilizing calculated solubility
parameters or empirically via the use of analytical techniques such as Fourier transform
infrared spectroscopy (FTIR) [53-55]. These interactions provide thermodynamic stability
to the amorphous drug substance and can result in product stability irrespective of Tg [56].
Drug loading can impact both kinetic and thermodynamic stability of an amorphous solid
dispersion. For a low Tg drug in a kinetically stabilized dispersion, the higher the drug
loading means the lower the composite Tg, and hence the more unstable the composition.
For a thermodynamically stabilized amorphous solid dispersion, increasing drug loading
can saturate bonding sites, and thus result in a less stable amorphous dispersion. Practically
speaking, most amorphous solid dispersions are formulated in a metastable region where
the mode of stabilization is a combination of both kinetic and thermodynamic mechanisms
[57]. As drug loading impacts both of these stabilizing mechanisms it is critical to conduct
accelerated stability studies on a range of drug loadings to arrive at a physically stable
amorphous dispersion with an acceptable drug load. Finally, packaging is critical when
the amorphous solid dispersion is susceptible to destabilization by moisture absorption
[58]. Adsorbed moisture can lead to crystallization by plasticizing the polymer matrix and
increasing the molecular mobility, displacing drug substances from bonding sites on the
polymer, or both. Utilizing the appropriate dosage form, the packaging configuration can
eliminate moisture contact and stabilize the amorphous product for an acceptable shelf-
life.
26
1.3 PROCESSES
1.3.1 Nano-crystal Technologies
Wet ball milling (also called bead milling or pearl milling) is the most frequently
used production method for drug nano-crystals in the pharmaceutical industry [59]. This
can be attributed in part to the simplicity of the process allowing it to be performed in
almost every lab. The simplest way of doing ball milling is feeding coarse drug substance
into a jar filled with milling media with at least one stabilizing agent. Then, agitate the
milling media by magnetic stirrer or by rotating or tumbling the jar. This will generally
yield very fine particles with a narrow size distribution when allowed to operate long
enough.
Alternatively, wet ball milling operations based on higher energy media movement
can accomplish particle size reduction in times more suitable for industrial pharmaceutical
applications [60]. The NanoCrystal™ process is a high energy wet ball milling process
regarded as the standard procedure to produce nanosuspensions [61]. To operate, the
milling chamber is filled with milling media, water, drug and stabilizer. A shaft with
projectiles spins within the milling chamber which allows drug particles to collide with the
chamber wall, milling media and other drug particles. The high shear forces provide the
energy input to fracture drug crystals into nanometer-size particles. Normal processing
times ranging from 30 minutes to 2 hours yield nanosuspensions of good quality. The
process has demonstrated scalability; batch mode R&D equipment can process 10 mg of
drug substance and larger continuous mode equipment is being used to produce
commercial products [62]. Because it is part of the process, one inherent benefit of wet
ball milling is creating a very stable aqueous suspension. This suspension can be directly
formed into liquid oral, injectable and nebulized inhalation delivery forms [63].
27
High pressure homogenization can be considered the second most frequently used
technique to produce nano-crystals [59]. Like wet ball milling, it is a particle size reduction
technology, but uses jet-stream homogenization by pumping drug, dispersion medium,
surfactants and/or stabilizers under high pressure through a micro fluidizing nozzle. The
particle size reduction is caused by cavitation forces, shear forces and collision through
multiple homogenization cycles. The number of passes depends upon many factors
comprising the type of homogenizer and process conditions, which has led to various
technologies: IDD-P™, Dissocubes® and Nanopure® [32].
Combination technologies have also been developed that integrate a pre-treatment
step with a subsequent high energy step, like high pressure homogenization. The
NANOEDGE™ technology is one example that combines a first classical precipitation
step with a subsequent annealing step by applying high energy (high pressure
homogenization)[32]. The term annealing was used meaning nanoparticles achieve a lower
surface energy by application of energy followed by thermal relaxation. Other combination
technologies, bottom-up methodologies and other processes are available to produce nano-
crystal drug delivery forms [64-66].
1.3.2 Amorphous Dispersion Technologies
Processes for the preparation of solid amorphous dispersions can be categorized
into two general types: solvent methods and fusion or melting methods. With solvent
methods, solid dispersions are obtained by evaporating a common solvent from a drug and
carrier solution. In general, fusion methods heat a drug and carrier composition above their
melting or glass transition temperatures, mix at the elevated temperature, and then cool the
composition in such a way to keep the active ingredient in its amorphous state. Operating
temperatures for solvent techniques are generally lower than fusion techniques and are
28
advantageous for thermolabile drug substances. However, finding a common solvent is
not always straightforward. For example, in the case for solid dispersions for immediate
drug release, hydrophobic drugs are typically combined with hydrophilic carriers, which
can limit solvent selection. A secondary drying step is often required to reduce residual
solvent below accepted levels for safety issues. In addition, small amounts of residual
solvent could negatively affect drug chemical stability and can plasticize the solid
dispersion matrix to subsequently impact physical stability [45].
Practical applications of the solvent method are spray drying and freeze drying. In
spray drying, the drug and carrier solution is atomized into hot gas that causes the solvent
to evaporate resulting in spherical particles containing amorphous drug [67]. Freeze drying
or lyophilization is a technique in which the drug and polymer solution is frozen and the
solvent is sublimed under vacuum. Another solvent method is using a fluidized bed system
to coat multiparticulates (i.e., beads or pellets) with drug-carrier solutions resulting in
pellets with a solid amorphous dispersion coating [68].
Hot-melt extrusion (HME), a well-known fusion technique, has been a topic of
interest in recent pharmaceutical research literature [69]. HME is the process of pumping
compositions through a heated barrel by one or more screws under pressure followed by
discharging the extrudate through a die. Solvents are not necessary thereby eliminating the
aforementioned solvent related issues. The intense mixing and agitation imposed by the
rotating screw(s) causes uniform distribution of drug and the processes is continuous and
efficient. The extrudate discharge is dense and can be post-processed without the bulk
density issues of some solvent methods. Viscous compositions may require the aid of a
plasticizing agent to allow the composition to flow through the heated barrel and out the
die without over torqueing the electric motor. Plasticizers increase molecular mobility
29
upon storage and can allow for crystallization if the composition’s glass transition
temperature is not at least 50°C above the storage condition [52].
Other fusion processes have been explored in creating amorphous dispersions.
Spray congealing is a process where molten compositions are atomized into particles of
spherical shape and then cooled to solidification [70]. KinetiSol® Dispersing is a fusion
based process that has been shown to create amorphous dispersions of high temperature,
thermolabile drug substances without degradation [71]. It does not have the same viscosity
limitations as HME and thus compositions are processed without the need of a plasticizer.
Scalability is a non-issue as the equipment is used in non-pharmaceutical industrial
applications, but no current marketed products are produced by this technology.
30
1.4 RESEARCH COMPARISONS
Numerous papers have been published on amorphous solid dispersions and nano-
crystal formulations. For the purposes of this comparison review, only original research
papers that directly compare the two in a formulation development effort are discussed.
Additionally, literature was limited to those studies that included participation and/or
support from a pharmaceutical company as this was considered to be an indicator of the
study’s commercial relevance.
Fakes et al reported on the enhancement of an HIV-attachment inhibitor, BMS-
488043 [72]. The molecule was classified as a BSC class II compound with low aqueous
solubility of 0.04 mg/ml and a permeability of 178 nm/s in a caco2 cell-line model. To
increase bioavailability of the molecule, a nanosuspension formulation was developed and
compared to an amorphous solid dispersion made by a solvent evaporation method. The
nanosuspension formula was produced by a Nanomill™ at a 10% (w/w) concentration
using hydroxypropyl cellulose (HPC-SL) at 2% (w/w) and sodium lauryl sulfate (SLS) at
0.1% (w/w). The mean cumulative particle size was 0.120 µm and the suspension was
physically stable when stored at room temperature up to 4 weeks.
The amorphous dispersion was produced by flash evaporation from an acetonitrile
solution in a Buchi Rotovap. Polyvinylpyrrolidone (PVP, K-30) was the selected polymer
with drug loadings of 20 and 40%. The dispersions were determined to be XRD amorphous
following storage at 50 °C up to 3 weeks. Further, an extremely high drug load amorphous
dispersion of 80/20 BMS-488043/PVP was found to remain amorphous after storage at 50
°C for 17 weeks. The two amorphous formulations and a single nanosuspension formula
were compared to wet-milled crystalline drug capsule in a crossover beagle dog study. The
two solid dispersions were dosed as 200 mg tablets with the nanosuspension administered
via a standard gavage tube at the equivalent dose. The nanosuspension showed a 4.7 fold
31
increase in Cmax and 4.6 fold increase in AUC over the capsule. The 20% amorphous
dispersion showed an 18.2 and 7.0 fold increase in Cmax and AUC respectively. The 40%
dispersion showed a 15.7 fold increase in Cmax and 8.7 fold increase in AUC. The authors
concluded that the amorphous dispersions were the superior option for increased
bioavailability of BMS-488043.
Zheng et al reported on the commercial development of LCQ789, a BCS Class II
compound, investigated particle size reduction, amorphous dispersions, lipid based
formulations and co-crystals [73]. LCQ789 is a crystalline, neutral compound with a
molecular weight of 476.93 and a ClogP of 5.4 with extremely low solubility (<1 µg/ml).
Each formulation method was carefully screened: co-crystal screening was performed with
four solvents and 27 co-crystal formers, solid dispersion screening was conducted with
seven polymers and a total of 64 variants, and lipid-based formulations were screened with
25 GRAS listed excipients. Particle size reduction on a research compound from the same
scaffold at LCQ789 showed minimal impact on its oral bioavailability, as confirmed by
GastroPlus™ and in vivo rat study. Consequently, the nanoparticle approach was not
pursued for LCQ789.
Optimized formulations were compared in rat and dog single dose pharmacokinetic
studies. Minimal exposure was observed with suspensions of crystalline LCQ789 and co-
crystal formula in rats, but the co-crystal did show some improved exposure in dogs. In
both species, significant improvement in bioavailability was achieved with the solid
dispersion and lipid-based formulations. The in vivo pharmacokinetic studies indicated
that the solid dispersion improved the oral bioavailability by 18-fold in rats and 50-fold in
dogs, while the lipid-based formula increased the oral bioavailability by 25-fold in rats and
80-fold in dogs. The lipid-based formula achieved the highest exposure, and the solid
dispersion demonstrated less inter-subject variability. These two formulas continued on to
32
dose escalation studies. Higher exposure was achieved with the lipid-based formula, but
it also exhibited higher variability as compared to the solid dispersion. In addition, overall
high organic content was a concern for the long-term safety studies. As a result, the solid
dispersion formulation was selected for use in safety studies.
Vogt et al investigated micronization, co-grinding and spray-drying formulations
of fenofibrate and compared their release profiles to German and French commercial
products [74]. Micronization was conducted by jet milling while nanosizing was
performed by bead milling. Co-grinding was achieved by particle size reduction with
lactose, polyvinylpyrrolidone (PVP), sodium lauryl sulphate (SLS) and combinations of
the three excipients. Spray dried particles were produced by bead milling with lactose and
SLS in water, then fed directly into a Buchi Mini Spray Dryer. All formulations were
compared by dissolution in biorelevant media. The fenofibrate drug products
commercially available on the German and French markets dissolved similarly to crude or
micronized fenofibrate and were slower than the co-ground and spray-dried formulas. The
co-ground formulations had faster dissolution rates, but reached the same equilibrium
concentration as the commercially available products. The spray-dried formula produced
substantial initial supersaturation, but returned to concentrations only slightly better than
equilibrium in 180 minutes because formulation did not contain a parachute component.
This was termed as unstable by the authors, but they concluded that both co-grinding and
spray-drying could potentially lead to better bioavailability of fenofibrate drug products.
Kwong et al reported that toxicity is one of the leading causes of attrition in the
clinic, and that good safety margins are imperative to reach proof of concept in clinical
studies [75]. Research was conducted to identify a conventional formulation that would
provide the maximum exposure possible to define the dose limiting toxicity for a molecule
referred to as compound 3. Compound 3 existed as a crystalline free base with poor
33
solubility in water (0.0002 mg/ml in water, 0.0003 mg/ml in SGF and 0.004 mg/ml in
FaSSIF), but was highly permeable. Thus, drug dissolution was the rate limiting step for
absorption.
Figure 1.3: Dose proportionality of compound 3 in 10% Tween (-▲-) as the crystalline
form; in 0.5% Methocel/0.24% SLS as the amorphous form (-■-) and in
solid dispersion at 50% drug loading in HPMC-AS given as suspension in
Methocel (-●-) from 10 mpk to 750 mpk dosed at 5 ml/kg in Sprague
Dawley rats (n=4) [75] (corrected).
Various preparation methods and excipients were screened and the leading
formulations were compared in a preclinical dose range finding study in rats. The three
leading formulas were (1) crystalline form in 10% Tween 80, (2) amorphous form in 0.5%
methylcellulose and 0.24% sodium lauryl sulfate and (3) a solid dispersion with 50% drug
loading in HPMCAS-HF as seen in Figure 1.3. The particle size for compound 3 was not
specifically mentioned; however, looking at another reported project within the article, the
particle size is conservatively below 10 µm. At the lowest dose, 10 mpk, the exposure was
similar for all three compounds. As the dose was increased to 100 mpk, the solubility of
the crystalline phase limited the absorption of the compound and resulted in a lower
exposure. It is interesting to note that the exposure obtained from the amorphous form is
34
comparable to the solid dispersion at this level. Finally, at 750 mpk the amorphous
dispersion provided a significant increase in exposure over the other two formulations (4x
AUC as compared to the crystalline phase).
Thombre et al compared amorphous, nanocrystalline and crystalline formulations
of ziprasidone to commercially available Geodon® capsules in order to minimize food
effect [76]. The three formulations in the study were (A) an amorphous inclusion complex
of ziprasidone mesylate and a cyclodextrin, (B) a nanosuspension of crystalline ziprasidone
free base made by wet-milling, and (C) jet-milled ziprasidone HCl coated crystals made by
spray drying the drug with hypromellose acetate succinate. The pharmacokinetic studies
in dogs showed that the three formulations performed differently. Formulation B yielded
the best fasted state absorption enhancement, indicating that improved dissolution rate with
a low potential for precipitation might be the best combination to improve ziprasidone
absorption in the fasted state. The in vivo data for formulation B was highly variable, but
the mean summary parameters were comparable to the control capsule dosed in the fed
state.
Formulation A also showed increase absorption of ziprasidone in the fasted state
compared to the commercial capsule. Because of the solubilization technology used,
ziprasidone likely went quickly into solution and was absorbed (formulation A had the
shortest observed Tmax). But, the extent of absorption was less than the control capsule
dosed in the fed state, indicating possible precipitation in intestinal pH media. In vitro
testing demonstrated that some amorphous complex formulations can achieve high enough
supersaturation to cause precipitation of a lower solubility drug form such as the free base.
Formulation C did not show enhanced absorption in the fasted state compared to the
commercial capsule control.
35
In humans, both formulations A and B showed improved absorption in the fasted
state while formulation C did not [77]. Thus, the in vivo performance in dogs was
qualitatively similar to the in vivo performance of these formulations in humans.
Sigfridsson et al compared crystalline and amorphous nanosuspensions to a
solution of AZ68 [78]. AZ68 is a neurokinin NK receptor antagonist intended for
schizophrenia treatment. The compound has high permeability and low solubility in the
gastrointestinal track and thus fulfills the criteria for a BCS II compound. Crystalline
nanosuspensions were prepared by bead milling; amorphous nanosuspensions were
prepared by a solvent evaporation process and confirmed amorphous by XRPD (Powder
X-ray Diffraction). Particle sizes for both suspensions were approximately 200 nm and
both formulations were dosed in rats by gavage at similar concentrations. The results
indicate that AZ68 is absorbed at a lower rate for crystalline nanosuspensions compared to
amorphous nanosuspensions and solutions. However, the absorbed extent of the
compound is similar.
36
1.5 MARKETED PRODUCTS
1.5.1 Nano-crystal Products
Perhaps the best way to understand the utility of a technology is to review its
application in marketed products. Table 1.1 contains examples of current marketed
products produced using nano-crystal technologies.
Table 1.1: Examples of commercial nano crystal products [59]
The first commercial product using a pure nanoparticle technology was
Rapamune®, a tablet formulation containing the immunosuppressant drug, sirolimus. It
was originally marketed as an unpleasant tasting lipid based liquid solution that required
cold storage and a dispensing protocol. Sirolimus is poorly water soluble (~2 µg/ml) and
processed by NanoCrystal® technology into a fine nanoparticle dispersion with a mean
particle size of <200 nm. The NanoCrystal Colloidal Dispersion® intermediate is then post
processed into tablets of 1 mg, 2 mg and 5 mg. The tablets have increased bioavailability
(~ 27%), do not require special storage conditions and have better patient compliance due
to a more convenient dosage form [62, 79].
The second product, Emend®, is an antiemetic for the prevention of nausea and
vomiting following chemotherapy and surgery. It is a spray coated capsule formulation of
aprepitant that has been formulated as a nanosuspension. Aprepitant (water solubility 3-7
Trade Name Generic Name Processing Technology Company FDA Approval
Rapamune Sirolimus NanoCrystal Pfizer (Wyeth) 2000
Emend Aprepitant NanoCrystal Merck 2003
Tricor Fenofibrate NanoCrystal Fournier Pharma (AbbVie) 2004
Triglide Fenofibrate IDD-P Sciele Pharma, SkyePharma 2005
Megace ES Megestrole acetate NanoCrystal PAR Pharmaceuticals 2005
Invega Sustenna Paliperidone palmitate NanoCrystal Janssen 2009
37
µg/ml) is a free base crystalline compound that was processed into a fine particle dispersion
using a wet milling technology, and then processed into a solid dosage capsule formulation.
The original dosage form showed significant food effect with exposures of 3-fold increase
under fed conditions for a 100 mg dose. The food effect was significantly higher at a 300
mg dose [80]. The NanoCrystal® formulation was able to eliminate the food effect by
increasing surface area 40 fold which resulted in a 4 fold increase in AUC values in the
fasted state of beagle dogs. The elimination of the food effect for antiemetic drug is
significant as the commercial success may have been limited if required to consume with
food [62].
Tricor® is the successor product for fenofibrate (for hypercholesterolemia) after
patent expiration. Triglide is also a fenofibrate nano-crystal product, but produced by the
IDD-P® technology. Tricor® has a dose of 48 mg or 145 mg in a tablet form. The nano-
crystal technology provided a life-cycle extension in the creation of a superior performing
product. Fenofibrate showed 35% higher absorption in the fed state and significantly
reduced the food effect [32].
Megace ES® (ES stands for enhanced solubility) is for the delivery of megestrol
acetate, a synthetic progestin used to treat anorexia, cachexia and AIDS-related wasting.
The commercial formulation is an aqueous nanosuspension. The dose is 625 mg/ 5 ml and
the nanosuspension reduces bioavailability differences between fed and fasted conditions.
It also has less administration volume than the previously given oral formulation (only ¼)
while being less viscous [32].
The last approved nano-crystal product to be discussed is Janssen’s INVEGA®
SUSTENNA®. This product, an atypical antipsychotic, is a once monthly intramuscular
extended release injectable dosage form of paliperidone palmitate. It is a liquid dispersion
product in prefilled syringes that has physical stability without the need for special storage
38
conditions for a two year shelf life. This is a sterile product by way of conventional
sterilization methods. Terminal heat is the preferred route, but filtration, gamma irradiation
and aseptic approaches are employed as alternatives [81]. The particulate nature of the
formulation allowed for sustained release and in a patient population where compliance is
a concern, the once a month dosage is a valuable option [62].
1.5.2 Amorphous Dispersion Products
Table 1.2 contains examples of current marketed products produced using solid
amorphous dispersion technologies. Trade Name Generic Name Processing Technology Company FDA Approval
Cesamet Nabilone Solvent evaporation Meda Pharmaceuticals 1985
Sporanox Itraconazole Fluid bed bead layering Janssen 1992
Prograf Tacrolimus Spray drying Astellas Pharma 1994
Kaletra Lopinavir, ritonavir Melt extrusion AbbVie 2007
Intelence Etravirin Spray drying Janssen 2008
Zortress Everolimus Spray drying Novartis 2010
Norvir tablet Ritonavir Melt extrusion AbbVie 2010
Onmel Itraconazole Melt extrusion Merz Pharma 2010
Incivek Telaprevir Spray drying Vertex 2011
Zelboraf Vemurafenib Solvent/anti-solvent precipitation Roche 2011
Kalydeco Ivacaftor Spray drying Vertex 2012
Table 1.2: Examples of current amorphous dispersion products [82] (modified).
The original solid oral formulation of Kaletra® was a soft-gelatin capsule (SGC)
containing 133.3 mg of lopinavir (an HIV protease inhibitor) with 33.3 mg of ritonavir,
with ritonavir acting as a bioavailability enhancer for lopinavir [83]. The SGC dosage form
required refrigeration and the recommended adult dosage was 6 capsules daily with food
to maximize the bioavailability of lopinavir. Toward the end of end of enhancing therapy
39
with Kaletra, the product was reformulated as a solid amorphous dispersion utilizing HME
technology. The result was a 200/50 mg lopinavir/ritonavir tablet formulation that reduced
the number of dosage units and eliminated the requirement for refrigeration. Compared
with the SGC formulation, the HME formed tablet resulted in more consistent lopinavir
and ritonavir exposures across meal conditions, which minimized the likelihood of extreme
high or low blood plasma concentrations. In addition, the removal of the refrigeration
requirement allowed for worldwide distribution into underdeveloped areas that could not
support a cold distribution chain.
The path toward the development of ritonavir into a solid oral dosage form based
on amorphous solid dispersion technology was very similar to that of Kaletra. Ritonavir
was originally developed because it possesses anti-HIV activity, but it is no longer
prescribed as a sole protease inhibitor in antiretroviral regimens today. However, as a
pharmacokinetic enhancer, ritonavir has become a mainstay in the management of both
treatment-naïve and treatment-experienced patients. The basis for this enhancement is the
inhibition of cytochrome P-450 (CYP) metabolic pathways [84]. Inhibition of CYP 3A4
leads to a reduction in the metabolism of most protease inhibitors and increases
pharmacokinetic properties including area-under-the-plasma concentration curve (AUC),
maximum plasma concentration (Cmax), and half-life (t½). These enhancements allow for a
reduction of pill burden, dosing frequency and food restrictions while maintaining efficacy.
Because ritonavir is not bioavailable in the crystalline solid state, it was formulated
in ethanol/water based solutions. It was available as an oral solution in 1996 and as SGC
since 1998. Only one crystal form of ritonavir was identified during development and the
initial 240 lots of Norvir® capsules had no stability problems [85]. However, in mid-1998
several lots of capsules failed the dissolution requirement and investigation revealed a
polymorph with greatly reduced solubility compared to the original crystal form. Within
40
weeks, this new polymorph (Form II) appeared throughout both the bulk drug and
formulation areas. Since the manufacturing of Norvir® capsules required a certain
concentration in the ethanol/water solutions, Form II made the formulation unproducible.
With the emergence and dominance of polymorph Form II, Abbott Laboratories
reevaluated their manufacturing process [86]. They reported a new method to control the
conversion of Form I to Form II by choosing an appropriate ratio of solvent to antisolvent
in a reactor process. Following the HME formulation development for Kaletra® in 2005,
Abbott began developing a 100 mg HME-based amorphous dispersion formula for
ritonavir. In the bioequivalence studies, the HME tablet demonstrated equivalence with
SGC for AUC parameters. However, the ritonavir tablet Cmax was 26% higher than the
SGC formulation [84]. This increase in Cmax was not expected to alter the safety or
pharmacokinetic enhancing profile of ritonavir. The tablet also exhibits less food effect
than the SGC formulation.
Itraconazole is another interesting example of a drug product that was
commercialized using an amorphous solid dispersion technology. The compound is a
potent broad-spectrum triazole antifungal drug, is insoluble in water (solubility ~4 ng/ml)
and was among the first marketed solid amorphous dispersion products. Itraconazole is so
insoluble in intestinal fluids that drug therapy with the compound could not be achieved
without substantial solubility enhancement by formulation intervention. The original solid
oral formulation, Sporanox® Capsule, was produced by a fluid bed bead layering process
that used a co-solvent system of dichloromethane and methanol to dissolve itraconazole
and hydroxypropyl methylcellulose (HPMC) which was then sprayed on inert sugar
spheres [87]. The resultant product provided a significant enhancement of itraconazole
bioavailability with approximately 55% of the administered dose absorbed [88].
Itraconazole has recently been reformulated into a tablet composition that contains an
41
amorphous dispersion in HPMC 2910 by HME utilizing the MeltRx Technology®. The
trade name is Onmel®; it is available in a 200 mg strength for once-daily administration
and was approved by the FDA in April 2010 for the treatment of onychomycosis. The
HME formulation not only eliminated the use of organic solvents in manufacturing, but
also reduced dosing frequency from twice-daily to once daily [89].
Like itraconazole, Zelboraf™ is another compound for which the drug therapy was
enabled by the application of amorphous solid dispersion technology. The product is a
tablet dosage form containing an amorphous dispersion of vemurafenib in HPMCAS-LF
produced by a solvent/anti-solvent precipitation called microprecipitated bulk powder
(MBP) technology [90]. The process utilizes N,N-dimethylacetamide to dissolve the drug
and the ionic polymer. The solution is precipitated into acidified aqueous media, the
precipitates are then filtered, repeatedly washed to remove residual acid and solvent
content, dried, and then milled to form the amorphous powder intermediate, MBP. The
MBP product provides substantial enhancement of the solubility/ dissolution properties
and oral bioavailability of vemurafenib with excellent physical stability. The stability of
the amorphous dispersion is attributed to the high composite Tg, intermolecular interactions
between the drug and polymer as well as the moisture protective effect provided by the
polymer.
In initial Phase I clinical studies with a conventional formulation of vemurafenib,
patients did not respond, i.e. no tumor regression, to doses as high as 1,600 mg [91]. The
issue was identified as low oral bioavailability stemming from poor solubility, which
caused a halt to the clinical study until it could be reformulated into a more bioavailable
form. Due to melting point and organic solubility limitations, traditional amorphous solid
dispersion processes could not be applied, therefore necessitating the application of the
MBP technology. When clinical trials resumed with the new MBP-based formulation,
42
substantial tumor regression was achieved in a majority of patients as a result of the
enhanced formulation [92]. The application of the MBP technology to vemurafenib is a
compelling case study for the application of amorphous solid dispersion technology
because formulation intervention was directly responsible for enabling the drug therapy
and prolonging the lives of terminal patients suffering from metastatic melanoma.
Figure 1.4: Timeline of FDA approved amorphous dispersion and nano-crystal
products.
In concluding this section, viewing the nano-crystal and amorphous dispersion
FDA approved products on a timeline might indicate a possible trend in the drug
development industry (see Figure 1.4). From this analysis, it appears poorly water-soluble
drug candidates were formulated for commercialization in the 1980s and 1990s using solid
amorphous dispersion technologies. In the late 1990s it seems as if the industry turned to
nano-crystalline technologies as the method of choice for development of BCS class II and
IV active ingredients. However, from 2006 to 2012 only one nano-crystal product was
approved by the FDA while 8 amorphous solid dispersion products were accepted.
43
Additionally, the last two FDA approved nano-crystal products were suspensions; the last
one being an intramuscular injection product. This is a small sampling, but it looks like the
current industry preference for solving water-solubility challenges for oral delivery is
through the use of amorphous solid dispersion technologies.
44
1.6 CONCLUSION
Nano-crystal delivery forms and amorphous solid dispersions are well established
techniques for addressing poor water solubility in pharmaceutical compounds, however,
the methodologies are quite different. While several marketed products are made by both
nano-crystal technologies and amorphous solid dispersion technologies, it appears there
are more amorphous dispersion products on the U.S. market today. A timeline of FDA
approved drugs suggests current industry preference for solving solubility challenges for
oral delivery is leaning toward amorphous solid dispersion technologies.
45
Chapter 2
New Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for
Poorly Water-soluble Drug Delivery (Part 1)
2.1 INTRODUCTION
Poor water solubility has been documented as a common characteristic for new
chemical entities in development pipelines and commercially available products in the
pharmaceutical industry today [2-4]. Among the options for dealing with poor solubility,
the incorporation of the drug substance in a solid amorphous dispersion dosage form is
gaining popularity. There are many reasons for this increase in popularity with only a few
being mentioned here. First, conventional chemistry methods for solubility enhancement
like salt formation reportedly only work for 20-30% of new molecules, leaving the 70-80%
remaining to find other routes to improved solubility [11]. Second, solid dispersions
containing solubility enhancing polymers can dramatically increase apparent solubility for
durations sufficient to enable absorption form the intestinal lumen. Specifically, in the case
of ITZ, solubility increases of 10,000 fold or more have been demonstrated [40-42]. Third,
nano-crystal technologies have not proven as capable and industry trends show preference
to solid dispersions [1]. Fourth, compared with other noncrystalline drug delivery
approaches such as cosolvent systems or self-emulsifying drug delivery systems (SEDDS),
amorphous solid dispersions are more amenable to be developed into tablets, which is the
preferred solid dosage form for distribution, and amorphous dispersions demonstrate
highly desirable advantages over liquid or semisolid formulations including lower
manufacturing cost, smaller pill burden, and improved physical and chemical stability [57].
Finally, the various grades of polymers used for solid dispersions can not only increase
solubility, but also allow for targeted release and the tailoring of release profiles of a drug
substance. Thus, solving multiple problems simultaneously.
46
While numerous studies have been published on amorphous solid dispersions, there
are a limited number of polymers suitable for creating those systems. Polymers that have
been reported as a major component in solid dispersion formulations for improved
solubility are as follows: povidone (PVP) [93], copovidone (PVPVA) [94], crospovidone
(CrosPVP) [95], polyethyleneglycols (PEG) [96, 97], polymethacrylates [98, 99],
hydroxypropylmethylcellulose or hypromellose (HPMC) [87, 89], hypromellose acetate
succinate (HPMCAS) [100, 101], hypromellose phthalate (HPMCP) [102],
hydroxyethylcellulose (HEC) [103], hydroxypropylcellulose (HPC) [104], polyvinyl
acetate phthalate (PVAP) [42], cellulose acetate phthalate (CAP) [42], poloxamers [105],
carbomers [106], and Soluplus® [107]. As additional polymers are identified as options, a
broader range of challenging drug substances may be enabled for oral delivery systems.
Furthermore, existing prohibitive intellectual property could be circumvented and unique
release profiles could be created. Due to the high cost of development and regulatory
compliance verification, repurposing an existing excipient would seem a financial and time
efficient path.
Polyvinyl Alcohol (PVAL) is a water-soluble synthetic polymer represented by the
formula (C2H4O)n. The value of n for commercially available materials is between 500 and
5,000, which is roughly equivalent to a molecular weight range of 20,000 to 200,000 [108].
PVAL is unique among the vinyl polymers in the fact that the monomer, vinyl alcohol,
cannot exist in the free form. So, it is manufactured by the polymerization of vinyl acetate
and then converted by a hydrolysis (alcoholysis) process. Various grades based on extent
of hydrolysis exists with unconverted fractions being polyvinyl acetate. Since EMD
Millipore PVAL was used in this research, a brief explanation of their nomenclature is
prudent. Each grade of PVAL has two groups of numbers separated by a dash. The first
group of numbers represents the viscosity of the 4% aqueous solution at 20 °C as a relative
47
indication of the molar mass. The second group of numbers is the degree of hydrolysis of
the polyvinyl acetate. For example, an 88 in the second group would represent 88%
hydrolysis with 98% being considered a fully hydrolyzed grade. Thus, a 5-88 grade would
have the viscosity of 5 mPa·s in a 4% aqueous solution at 20 °C with the polymer chain
being approximately 88% PVAL and 12% polyvinyl acetate [109]. Table 2.1 contains
additional properties.
Available molecular weights 14,000 – 205,000 g/mol for partially hydrolyzed grades; 16,000 – 195,000 for
fully hydrolyzed grades.
Crystallite melting point (Tk) 180 – 240 °C
Glass transition temperature (Tg) 40 – 80 °C
Percent crystallinity Varies; increases with percentage hydrolysis.
Solubility in water Solutions can be prepared at any concentration. However, because viscosity
rises rapidly with solids content, certain practical limits exist for processable
solutions.
Solubility in organics Insoluble in most organic solvents. Slightly soluble in ethanol, practically
insoluble in acetone.
Temperature onset of degradation Approximately 180 °C
Aqueous solution pH (4% solution at room temperature) 5.0 – 6.5
Hygroscopicity DVS measurements reveal below a relative humidity of 50%, the change in
mass is less than 1%. At 90% relative humidity, mass changes of 8 – 17%
depending upon polymer type.
Table 2.1: Properties of PVAL (EMD Millipore) [109]
PVAL is currently being used in a variety of pharmaceutical applications. It is used
as a stabilizing agent for emulsions [110], in topical pharmaceutical [111] and ophthalmic
formulations [112, 113]. It is used in artificial tears [114] and integrated into contact lenses
for lubrication purposes [115]. Polyvinyl alcohol can be made into microspheres [116] and
is used as an emulsifier in creating PLGA nanoparticles [117, 118]. It has also been used
in sustained-release formulations for oral administration [119] and transdermal patches
[120]. Oral toxicity has been evaluated and found safe even at high levels of consumption;
48
the no-observed-adverse-effect level (NOAEL) for rats in a 3 month study was 5,000
mg/kg body weight / day [121].
To the authors’ knowledge, PVAL has not been reported as the polymeric carrier
in binary amorphous solid dispersions [122]. A brief discussion of the limitations of
conventional methods for creating amorphous dispersions provides insight to probable
reasons for this. Solvent processes (e.g., like spray drying and precipitation approaches)
require a drug/polymer solution prepared with a common solvent or co-solvents. PVAL is
insoluble in most organic solvents and only slightly soluble in ethanol while typical
pipeline drug molecules are only slightly soluble in more aggressive organic solvents.
Even if suitable solvents were ascertained, the required concentration of polymer would
render the solution too viscous for practical processing (like preventing flow through a
small orifice needed for spray drying). Alternatively, the application of conventional
fusion processes like hot melt extrusion (HME) and injection molding is limited due to the
high melting point of PVAL and high viscosity of the resulting melt. These technologies
are not suitable for processing thermally sensitive and viscous formulations, however
KinetiSol® has been demonstrated in these applications [123]. KinetiSol® Dispersing is a
novel fusion process that does not have torque limitations like HME and has been shown
to create unique solid dispersions [71]. Through this enabling technology, solid amorphous
dispersions containing PVAL as the primary polymer can now be evaluated.
The pH independence of PVAL presents some advantages in bioavailability
enhancement. The dissolution of pharmaceutical excipients with pH dependent ionizing
properties can be variable across the gastrointestinal pH range [124]. For example,
dissolution rate and apparent solubility of weakly basic drugs in gastric pH and weakly
acidic drugs in intestinal pH would be higher due to the ionization at those pH conditions
[40, 41, 125]. Anionic and cationic polymers are prone to those same ionization effects,
49
which allows for differing dissolution rates across the gastrointestinal tract. This may
become clinically significant for formulations utilizing ionic polymers in both inter-patient
and intra-patient variation. The dissolution behavior of non-ionic polymers is expected to
be the same across the gastrointestinal track, which should lower variability and provide a
more predictable bioavailability improvement [126]. Anionic polymers, even with
variation challenges, are still often chosen in formulation development due to their ability
to improve solubility compared to non-ionic polymers [127]. Anionic polymers have been
shown to increase dissolution rate and apparent solubility of both weakly basic and neutral
drugs in amorphous dispersions due to polymer/drug interactions likely occurring between
polymer functional groups and the drug substance [128]. The few non-ionic polymers
used for solid dispersions, primarily HPMC, PVP and PVPVA, do not exhibit tunable ratios
of hydrogen bond donors and receptors like HMPCAS and polymethacrylates. However,
PVAL has a tunable density of hydrogen bond donating hydroxyl groups and hydrogen
bond receptors along its polymer backbone while still having pH independent solubility.
In theory, this would allow it to function strongly as a solubility enhancer like the anionic
polymers, but also have the low variability of the non-ionic polymers.
It is hypothesized that the pH independent solubility along with tunable density of
functional groups of PVAL would be ideal in the creation of solid dispersions especially
for weakly basic drugs. While other groups have shown stability with semicrystalline
polymers, PVAL will need be investigated to establish the polymer crystalline structure
does not create nucleation sites for drug recrystallization during processing and storage
[129]. As a first step in investigating that PVAL will function as a solubility enhancing
polymer, ITZ was selected as the model drug to be formulated in various grades. Varying
molecular weight grades with identical degree of hydrolysis were used to create solid
dispersions to determine its effect on performance. Conversely, the best performing
50
molecular weight range of PVAL from the first group of formulations were selected in
grades of changing degrees of hydrolysis. The best performing polymer grade would then
be compared to commercially available ITZ products.
51
2.2 MATERIALS
Itraconazole was purchased from Hawkins, Inc. (Minneapolis, MN). All grades of
EMD Millipore PVAL were donated by Merck Millipore. All other chemicals used in this
study were ACS grade.
2.3 METHODS
2.3.1 KinetiSol® Dispersing (KSD)
All compositions for this study were produced by a lab scale, GMP pharmaceutical
compounder designed and manufactured my DisperSol Technologies, L.L.C.
(Georgetown, TX, USA). Prior to KSD processing, materials were weighed, placed into a
polyethylene bag, manually shaken for approximately 1 minute, and charged into the
compounder chamber. During processing, real time computer controls monitor various
parameters and eject the material at a pre-set ejection temperature. Discharged material
was immediately quenched in a cooling die under pressure in a pneumatic press. Cooled
material was then milled in a FitzMill L1A and screened through a 60 mesh screen (250
µm). All further analyses was conducted on this powder.
2.3.2 Differential Scanning Calorimetry (DSC)
Modulated DSC analysis was conducted using a TA Instruments Model mQ20 DSC
(New Castle, DE) equipped with a refrigerated cooling system and auto sampler. Samples
were weighed to 5 - 10 mg in aluminum-crimped pans. Samples were heated at a ramp rate
of 10 °C/min from 0 to 210 °C with a modulation temperature amplitude of 1.0 ºC and a
modulation period of 60 seconds for all studies. Ultrahigh purity nitrogen was used as the
purge gas at a flow rate of 50 mL/min. All data analyses were performed using TA
Universal Analysis software. The thermogram for amorphous ITZ used in the DSC analysis
52
of the solid dispersions formulations was obtained on a second heating of crystalline ITZ
following an initial heating to 200 ºC followed by rapid cooling (40 ºC/min) to 0 ºC.
2.3.3 Powder X-Ray Diffraction (XRD)
An Inel Equinox 100 X-ray diffractometer (INEL, Artenay, France) was used to
detect the presence of ITZ crystallinity. Milled compositions, physical mixtures or
unprocessed ITZ were loaded on a rotating aluminum sample holder and placed in the
radiation chamber. The Equinox 100 utilizes Cu K Alpha radiation (λ = 1.5418 Å) with a
curved radius detector to simultaneously measure a 2ϴ range of 5 - 110°. Operating voltage
and amperage were adjusted to 41 kV and 0.8 mA respectively and the scan time for each
sample was 10 minutes.
2.3.4 Polarized Light Microscopy (PLM)
While XRD has been shown to have limits of detection of less than 1% [130], PLM
can serve as a qualitative confirmation of XRD results. PLM analysis was conducted on a
Meiji Techno MT 9300 Polarizing microscope with a first order red compensator.
Pulverized samples were dusted on a glass slide and viewed under 400x magnification.
The slide holder was rotated at least 90 degrees while being observed to detect any light
refractions. Images were taken by an Infinity CMOS camera.
2.3.5 Size Exclusion Chromatography (SEC)
Molecular weights of PVAL in both processed and unprocessed samples were
analyzed with a Dionex Ultimate 3000 H/UPLC system equipped with a Shodex (Showa
Denko K.K., Japan) Refractive Index detector. Two Shodex Asahipak 7.6mm x 300mm
(GF-7M HQ) columns were placed series and maintained at 40 °C. A 50nM LiCl aqueous
solution was utilized at the mobile phase at a constant flow rate of 0.7 mL/min. Sample
injection volumes were 100 µL [131].
53
2.3.6 Non-sink Dissolution Analysis
Non-sink dissolution analysis was conducted with a VK 7000 dissolution tester
(Varian, Inc., Palo Alto, CA, USA) in accordance with USP XXXIV Method A for delayed
release dosage form. Solid dispersions (n=3) were weighed to achieve an equivalent of
37.5 mg ITZ and placed in dissolution vessels containing 750 ml of 0.1 N HCl (~10x ITZ
equilibrium solubility in acid) equilibrated to a temperature of 37.0 ± 1 °C with a paddle
rotation of 50 rpm. After 2 hours, a buffer medium of 250 mL of 0.2M Na3PO4, preheated
to 37.0 ± 1 °C, was added to the dissolution vessels to adjust the pH to 6.80 and reach 1000
mL in volume. Samples were taken at 1, 2, 2.25, 2.5, 3, 4 and 5 hours. Samples were
immediately filtered using 0.2 µm PTFE membrane, 13 mm filters, diluted to a 1:1 ratio
with mobile phase, mixed and then transferred into 1 mL vials for HPLC analysis.
2.3.7 High Performance Liquid Chromatography
The ITZ content in processed samples and dissolution aliquots were analyzed with
a Dionex Ultimate 3000 H/UPLC system equipped with diode array detector extracting at
263 nm. The system was operated under isocratic conditions with a 70:30:0.05
acetonitrile:water:diethanolamine mobile phase equipped with a Phenomenex Luna 5 µm
C18(2) 100 Å, 150 mm x 4.6 mm (Phenomenex, Torrance, CA) HPLC column. Dionex
Chromeleon 7.2 software was used to analyze all chromatography data.
2.3.8 In Vivo Studies
In vivo studies were conducted at Charles River Laboratories (Wilmington,
Massachusetts Facility) under NIH guidelines with IACUC approval. Male Sprague-
Dawley rats equipped with a surgically-implanted jugular vein catheters to facilitate blood
collection were prepared for the study. Animals were assigned to the study based on
catheter patency and acceptable health as determined by a staff veterinarian and placed into
54
groups of four animals (See Table 2.2 for details). All animals were fasted overnight prior
to dose administration and food was returned following the 4-hour post-dose blood
collection. All dosage forms were milled to a fine powder and suspended in an aqueous
dosing vehicle to insure accurate ITZ to rat body weight medicating.
Group
No.
No. of
Males
Treatment
Test Article Dose Level
(mg API/kg)
Dose Conc.
(mg API/mL)
Dose
Volume
(mL/kg)
Dose Vehicle Dose
Route
1 4 KSD
[ITZ:PVAL 4-88 (1:4)] 30 6 5 2% HPC/
0.1% Tween 80/
pH 2.0
Oral
gavage 2 4
Onmel™ tablets
(pulverized) 30 6 5
Table 2.2: Rat PK study design
Blood samples (0.25 mL; sodium heparin anticoagulant) were collected from the
jugular vein catheter or by venipuncture of a tail vein if the catheter became blocked. Blood
samples were collected from each animal at 2, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours following
oral dosing. All whole blood samples were placed on wet ice immediately after collection
and were centrifuged at 2-8ºC to isolate plasma. The resulting plasma was transferred to
individual polypropylene tubes and immediately placed on dry ice until storage at
nominally -20C before transfer to the Charles River’s Bioanalytical Chemistry
Department for concentration analysis.
Plasma samples were analyzed for itraconazole concentration using a proprietary
in-house research grade LC-MS/MS Assay. Pharmacokinetic parameters were estimated
from the plasma concentration-time data using standard noncompartmental methods and
utilizing suitable analysis software (Watson 7.2 Bioanalytical LIMS, Thermo Electron
Corp).
55
2.4 RESULTS AND DISCUSSION
2.4.1 Preliminary Evaluation of PVAL Molecular Weight
Due to the uniqueness of the KinetiSol® technology, screening methods do not exist
to determine the processability of a new polymer. So, three viscosity grades representing
a low (PVAL 4-88), medium (PVAL 26-88) and high (PVAL 40-88) with the same level
of hydrolysis were selected with an arbitrary ITZ loading of 20%. Because of the feasibility
nature of this study, KSD processing parameters were not optimized but considered
acceptable if ITZ was rendered amorphous as determined by XRD and PLM analysis and
drug assays were at least 96%. This was easily achieved for the 4-88 grade as the
discharged material was a single agglomerated, semi-molten mass similar in character to
other previously processed formulations. The 26-88 and 40-88 grades behaved differently
in that the discharged material was a slightly densified powder. Variance in processing
RPM or increases in discharge temperature would not render an agglomerated discharge
which is typical of the KSD processes (preliminary results not reported). Other polymers
with larger molecular weights have been used in previous research without incident [132].
Thus, this phenomena must be attributed to the specific sintering properties or crystalline
nature of high viscosity grades of PVAL. The addition of 4-88 to 26-88 as a minor
component allowed for an agglomerated discharge, however a 1:1 ratio of 4-88 to 40-88
was required to achieve the same result. For consistency, a 1:1 ratio of 4-88 to both 26-88
and 40-88 was chosen as the compositions to continue this portion of the study.
Size exclusion chromatography was performed on unprocessed polymer grades as
controls and on the KSD processed compositions of ITZ with 4-88, 4-88:26-88 and 4-
88:40-88. Comparison of unprocessed and KSD processed 4-88 is shown in Figure 2.1A
while comparison of unprocessed, one-to-one physical mixture of 4-88 and 40-88 to the
KSD process composition is shown in Figure 2.1B.
56
A
B
Figure 2.1: SEC profiles of unprocessed powders and processed compositions.
Peaks associated with polymer have been numbered, followed by the elution time
(longer elution times signifies a smaller molecular weight). Each sample was analyzed in
triplicate, and representative chromatograms are presented herein. Unprocessed 4-88 had
a peak elution time of 24.917 minutes compared to the KSD processed 4-88 with a peak
time of 24.638. The physical mixture of 4-88 and 40-88 exhibited a first polymer peak at
21.193 minutes, which corresponds with the 40-88 grade, and the second peak at 24.788,
which is associated with the 4-88. The KSD composition showed elution times of the
respective peaks at 21.103 and 24.407. The small difference in the times can be explained
by sampling variance and it can be concluded that KSD processing did not change the
57
molecular weight of PVAL. However, it was noted that the KSD compositions always
eluded at an earlier time compared to the corresponding unprocessed powder, which would
indicate a slight increase in molecular weight. It is plausible that a portion of the
solubilized ITZ remains bound on the polymer following dissolution of the sample in the
diluent and while traversing the column, which would increase the apparent size of the
polymer coil and manifest as an increase in molecular weight. The key result of this
analysis is that there is no indication of a reduction in the molecular weight of the starting
PVAL material after KSD processing.
Dissolution profiles of the three compositions were compared (data not shown).
The ITZ:4-88 and ITZ:4-88:26-88 compositions performed similarly, but the ITZ:4-88:40-
88 composition did not maintain ITZ supersaturation to the same extent following the pH
change. With its ease of processing and good dissolution profile, the 4 mPa·s grade of
PVAL was selected as the molecular weight to continue evaluation of the effect of degree
of hydrolysis on polymer performance.
2.4.2 Solid-state Analysis
Various hydrolysis grades of the same viscosity were selected for comparison with
4-88, namely 4-38, 4-75 and 4-98. Polyvinyl alcohol is known to be a crystalline polymer
and XRD profiles were generated for each polymer used in this study to determine the
effect of molecular weight and degree of hydrolysis has on the crystallinity (see Figure
2.2). The XRD data matches the reported information in that crystallinity does appear to
increase with degree of hydrolysis. The 4-38 grade, contains a greater component of
polyvinyl acetate than PVAL, is the only grade that is XRD amorphous. All the other
grades had a primary peak between 19 and 20 2-theta with two other easily distinguishable
peaks between 22 and 23 and between 40 and 42 2-theta. The 26-88 and 40-88 grades
58
showed larger peak intensities than the 4-88 grade that might indicate increased
crystallinity with molecular weight and would explain why these grades were more
difficult to process at the selected conditions. The 4-98 grade, which is the only fully
hydrolyzed grade, demonstrated the highest peak intensities of all the grades tested.
Figure 2.2: XRD profiles of PVAL grades used in study
XRD profiles were also generated for ITZ and the processed compositions as
illustrated in Figure 2.3.
Figure 2.3: XRD profiles of ITZ and KSD compositions
59
For the 4-38, 4-75, 4-88 and 4-98 compositions, the profile demonstrates that the
drug substance is amorphous while the polymers retain their crystalline structure. In the
compositions with a one to one polymer ratio of low molecular weight with higher
molecular weight (only the 4-88:40-88 profile is shown, but the 4-88:26-88 profile was
identical), the major crystalline peak is visible, but with lower intensity. Other peaks are
barely distinguishable. It appears that the combination of different molecular weights
interact in such a way as to reduce the crystalline structure of the polymer portion of the
composite.
mDSC analysis was conducted on the pure PVAL polymers to understand the
thermal characteristic of each grade prior to analyzing the ITZ:PVAL KSD compositions.
Considering that PVAL is a copolymer of polyvinyl acetate (PVAC) and PVAL one would
expect to see by DSC analysis a Tg of the PVAC component and a melting endotherm of
the crystalline PVAL component, the prominence of both being a function of the degree of
hydrolysis. That is to say that with increasing degree of hydrolysis, the Tg of the PVAC
component will be less pronounced and the melting endotherm of PVAL will be more
distinct. Thus, a fully hydrolyzed grade would exhibit essentially no Tg associated with
PVAC and a strong melting endotherm associated with PVAL. The DSC thermograms for
the four 4 mPa·s grades of PVAL and their corresponding KSD compositions provided in
Figure 2.4 (nonreversing heat flow) and Figure 2.5 (reversing heat flow) demonstrate this
expected trend.
60
Figure 2.4: Nonreversing Heat Flow DSC thermograms for 4 mPa·s grades of PVAL
Figure 2.5: Reversing Heat Flow DSC thermograms for 4 mPa·s grades of PVAL
It is seen that the 4-38 grade, which is predominantly PVAC, exhibits a strong Tg
associated with the PVAC component and no detectable melting endotherm for PVAL
[133]. The amorphous nature of this grade as demonstrated by DSC is in agreement with
the previously discussed XRD result. Hence, it is understood that below a critical degree
of hydrolysis the PVAL component is unable to interact with itself to form crystallite
structures due to the density of PVAC on the polymer chain. Examining the thermograms
for the 4-75 and the 4-88 grades, the expected trend is seen in that the Tg becomes less
noticeable and the melting endotherm becomes more pronounced with an increased Tm as
61
the degree of hydrolysis is increased: consistent with increasing crystalline content of the
polymer. The thermal profile obtained for the 4-98 grade matches industry literature for
fully hydrolyzed polyvinyl alcohol with a melting point around 223 °C. The reversing heat
flow profile for PVAL 4-98 shows a slight thermal event around 70 °C which others have
suggested was the Tg [134]. This event was much less prominent than the Tg events for 4-
88, 4-75 and 4-38 as would be expected considering the low PVAC content and was not
able to be accurately quantified by the analysis software. The DSC profile for the 4-98
grade corroborates the XRD result indicating high crystallinity of the fully hydrolyzed
grade.
mDSC analysis was performed on the ITZ:PVAL KSD compositions to investigate
the dispersed state of ITZ in each polymer grade and to evaluate the influence of the
dispersed drug on the thermal properties of the polymers. Figure 2.6 contains the
nonreversing heat flow thermograms for the KSD composition and ITZ while Figure 2.7
contains the reversing heat flow thermograms.
Figure 2.6: Nonreversing Heat Flow DSC thermograms for KSD compositions and ITZ
62
Figure 2.7: Reversing Heat Flow DSC thermograms for KSD compositions and ITZ
The nonreversing heat flow thermogram in Figure 2.6 shows a general trend of
broadening and/or reduction in the magnitude of the glass transition event for the 4-38, 4-
75 and 4-88 grades relative to the pure polymers. This could be attributed to dilution and/or
anti-plasticizing effect of the dispersed ITZ phase. Consistent with the pure polymer, a Tg
is not apparent for the KSD composition with the 4-98 grade. Also seen for each of the 4-
38, 4-75 and 4-88 grades is an exothermic event indicative of ITZ crystallization with peak
temperatures in the range of 117 – 127 °C. Interestingly, the magnitude of the exothermic
event is inversely proportional to the degree of hydrolysis. This suggest that the physical
stability of an ITZ amorphous dispersion in PVAL increases with increasing degree of
hydrolysis. One possible explanation for this is that increasing the degree of hydrolysis
increases the density of hydrogen bon donor sites on the polymer backbone that could
interact with the hydrogen bond acceptor sites on ITZ to form a stable complex [86].
Another possible explanation is that the amphiphilic character of the polymer that stems
from the ratio of hydrophilic PVAL-to-hydrophobic PVAC units approaches an optimum
with regard to stabilizing interactions with ITZ as the percent hydrolysis is increased up to
88%.
63
When the degree of hydrolysis is low, as with the 4-38 grade, the dispersed ITZ
phase would interact largely with the PVAC component which contains only hydrogen
bond acceptor sites (assuming hydrogen bonding is forming the complex). Therefore, in
this phase, the amorphous dispersion is stabilized by weaker intermolecular forces like Van
der Waals forces. If the stable complex is formed by hydrophilic/hydrophobic
microenvironments, then the fewer hydroxyl groups of the 4-38 grade would provide fewer
areas for interaction. In either case, these weaker intermolecular forces are more easily
disrupted by thermal perturbations; hence, post-Tg phase separation of amorphous ITZ and
subsequent crystallization during the temperature ramp is observed to a greater extent with
reduced degree of hydrolysis [135]. This is corroborated by the result for the fully
hydrolyzed grade in which a crystallization exotherm was not detected.
Figure 2.6 also shows that for all KSD processed compositions, a minor ITZ
endotherm was detected. For the KSD compositions with PVAL 4-38, 4-75 and 4-88, this
endotherm is similar in magnitude to the crystallization exotherm, which suggest that the
ITZ melting event is related entirely to ITZ that crystallized during the DSC scan. This
result validates the findings of XRD in which no crystalline ITZ was detected. In the case
of the 4-98 grade, where no crystallization exotherm was detected, the ITZ melting
endotherm is likely due to residual crystalline ITZ remaining after processing. This could
be due to incomplete dispersion of ITZ in the polymer on processing resulting from the
highly crystalline nature and/or the high Tm of the PVAL 4-98 grade. It could also be the
result of amorphous ITZ being forced out of its interaction with the polymer as the highly
crystalline grade returned to its preferred crystalline orientation on quenching. This result
appears to contradict the XRD analysis; however, considering its small magnitude, the
melting endotherm represents a small fraction of the dispersed ITZ, the crystalline peaks
of which could be easily masked by the high intensity peaks of PVAL 4-98.
64
Finally, it is interesting to note in Figure 2.6 the melting endotherms for the PVAL
4-75 and 4-88 are significantly reduced in comparison to the pure polymer; beyond what
would be expected for a 20% dilution on the addition of ITZ. This suggests that the
dispersed ITZ phase disrupts crystallization of PVAL upon cooling due to drug/polymer
interactions. A similar melting endotherm, in terms of magnitude, between the pure
polymer and the KSD composition for the 4-98 grade seems to suggest incomplete
disruption of polymer crystallinity on processing and/or displacement of ITZ during the
quenching process. Considering this, it seems that a sufficient fraction of PVAC on the
polymer is required to disrupt PVAL crystallite structure to facilitate a molten transition
by KSD processing and achieve a homogenous dispersion of the drug substance [136].
Additionally, PVAC units interspersed on the polymer backbone may act as defects within
the PVAL crystallite structure that effectively make available sites for drug/polymer
interactions [97]. However, one would expect to see a point of diminishing returns for
increasing PVAC concentration as this would also lead to weaker drug/polymer
interactions. From Figure 2.6, it would appear that this optimum PVAL:PVAC ratio for
ITZ is near that of the 4-88 grade.
The reversing heat flow shown in Figure 2.7 shows similar trends to those of the
nonreversing heat flow analysis, however with better resolution of the glass transition
events. Specifically, the Tgs of the KSD compositions with the 4-88 and 4-98 grades are
able to be resolved by reversing heat flow analysis and have respective midpoint values of
58.05 °C and 51.78 °C. Also provided in Figure 2.7 is a thermogram for pure amorphous
ITZ which shows a Tg of 59 °C followed by two endothermic events at 74 °C and 90 °C
that have been identified as mesophases of glassy itraconazole [137]. In comparing all of
the KSD compositions in the figure, the 4-88 grade has the highest composite Tg. The Tg
is more than 10 °C higher (roughly 20%) than KSD compositions with 4-38 and 4-75
65
grades as well as the pure 4-88 polymer and is close to the Tg of pure amorphous
itraconazole. The anti-plasticizing effect of amorphous ITZ on the 4-88 grade indicates
strong positive drug-polymer interactions [138]; most likely due to hydrogen bonding
between the acceptor sites on ITZ and the donor sites on PVAL. The increased Tg relative
to the other PVAL grades seems to also support the previously discussed hypothesis
regarding an optimal ratio of PVAC to PVAL at which hydrogen bonding or
hydrophilic/hydrophobic locations are maximized. From these results, it can be concluded
that 4-88 is the best performer of the PVAL grades tested from a thermodynamic
standpoint.
2.4.3 Non-sink, Gastric Transfer Dissolution Analysis
As discussed previously, PVAL is an interesting new carrier polymer in the area of
supersaturating amorphous solid dispersions owing to its non-ionic nature and the high
density of hydrogen bond donor sites on the polymer chain. These attributes make it a
particularly attractive concentration enhancing carrier for weakly basic drugs which have
been shown to interact strongly with anionic carrier polymers to yield substantial
improvements in apparent solubility [40]. To investigate the concentration enhancing
effects of PVAL on ITZ, the dissolution properties of the four KSD compositions were
evaluated by a non-sink, gastric transfer dissolution method. The results of this analysis
are presented in Figures 2.8 and 2.9.
66
Figure 2.8: Dissolution Profiles for 4 mPa·s grades KSD compositions
Figure 2.9: Dissolution Profiles for 4 mPa·s grades KSD compositions presented as
concentration (C) relative to the saturation concentration (Cs) of ITZ at the
respective pH.
Both the 4-75 and 4-88 compositions achieved complete drug dissolution before
the pH change at 2 hours, while the 4-38 and 4-98 grades did not. Polyvinyl acetate is not
67
water soluble, which would explain why 4-38 did not go into solution like the higher
hydrolyzed grades. Owing to its highly crystalline nature, the 4-98 grade dissolves at a
very slow rate under the dissolution conditions of this study; hence, ITZ release from this
composition is slow and incomplete. After the pH change, the 4-88 grade provided
superior concentration enhancing effect presumably due to the greater PVAL content on
the polymer and increased probability of ITZ interaction with the polymer in solution. The
4-38 and the 4-98 grades provided essentially no concentration enhancing effect due to the
low concentration of dissolved polymer in the dissolution medium. Contrasting the
dissolution AUCs after the pH change, gives a rank order of 4-88 > 4-75 > 4-98 > 4-38
with respective values of 640 ± 89, 442 ± 23, 130 ± 9 and 115 ± 8 mg·min. By way of
comparison, DiNunzio et al. reported a post pH change dissolution AUC for Sporanox®
capsules of 226 ± 23 mg·min [42]. In Figure 2.9, these dissolution results are presented in
terms of concentration at each time point (C) relative to the saturation concentration (CS)
of ITZ at the respective pH. It should be noted that the CS for ITZ decreases dramatically
from 5 µg/ml to 1 ng/mL when the pH of the media is changed from 1.2 to 6.8 [5]. When
plotted in this manner, the extent of supersaturation enabled by PVAL 4-88 at neutral pH
becomes quite evident with solution concentrations nearly 9,000 times the saturation
concentration of ITZ. These results therefore demonstrate that PVAL is an effective
concentration enhancing polymer for ITZ and support the hypothesis that hydrogen bond
donor sites are the key points of interaction with weakly basic compounds that provide
stabilization/prolongation of aqueous supersaturation.
2.4.4 In Vivo Study
From solid state and dissolution evaluation of PVAL grades with varying degrees
of hydrolysis, PVAL 4-88 emerged as the top performing polymer. In order to investigate
68
the effect of this polymer on the oral absorption of ITZ from an amorphous dispersion, the
pharmacokinetics (PK) following oral administration to a rat model of this binary
composition were comparatively evaluated against the commercially available ITZ
product, Onmel™. The plasma concentration versus time profiles generated from this study
are shown in Figure 2.10 while the key pharmacokinetic parameters as calculated by non-
compartmental analysis are provided in Table 2.3 with the addition of previously obtained
results for Sporanox®. Table 2.3 contains the plasma drug concentration AUC(0-last), AUC(0-
∞ ), Cmax and Tmax.
Figure 2.10: Rat PK of PVAL 4-88 compositions compared with Onmel™.
69
AUC(0-last)
(hr·ng/mL)
AUC(0-∞)
(hr·ng/mL)
Cmax
(ng/mL)
Tmax
(hr)
ITZ:PVAL 4-88 (1:4) 3,315 ± 1336 3,595 ± 1662 391 ± 111 3.88 ± 0.25
Onmel™ 2,565 ± 1374 2,624 ± 1391 367 ± 202 3.50 ± 1.22
Sporanox® (From
[42])
2,132 ± 1273 359 ± 261 5.5 ± 2.3
Table 2.3: Rat PK mean calculations
The mean AUC and Cmax for the PVAL 4-88 composition was greater than that of
Onmel™ and Sporanox®. However, it is noted that the drug loading of the ITZ:HPMC
dispersion in the Onmel™ tablet is double that of the PVAL 4-88 composition. Similarly,
the nonpareil beads in the Sporanox® composition are coated with a 40% w/w itraconazole
and 60% w/w HPMC solid dispersion [139]. Therefore, the contrast with commercial
products is not a true apple-to-apple comparison. Further studies will evaluate PVAL
compositions at 40% w/w loading to have a more comparable result. Yet, considering the
exploratory nature of this study, the analogous in-vivo performance of this first generation
PVAL composition to commercial products is noteworthy.
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2.5 CONCLUSION
This feasibility study has demonstrated that PVAL’s pH independent solubility
along with tunable density of functional groups allow it to function as a concentration
enhancing polymer, effectively increasing the apparent solubility of poorly water soluble
drug, itraconazole. The KinetiSol® technology enables the use of PVAL as the primary
carrier for amorphous solid dispersion compositions. Solid-state and non-sink dissolution
analysis revealed that the 88% hydrolyzed grade of PVAL was optimal for the ITZ
compositions. Pharmacokinetic analysis in a rat model demonstrated that the ITZ/PVAL
4-88 composition yielded exposures that were possibly superior to Sporanox® and
Onmel™.
Future research with ITZ will evaluate the effect of molecular weight in the range
between the 4-88 and 26-88 PVAL grades tested in this study on dissolution performance.
It will also explore increased drug loading levels, and evaluate storage stability. Additional
separate studies are planned to determine the broad application of PVAL evaluating
amorphous dispersions with neutral and weakly acidic drug substances. This
supplementary information would offer a foundation for development scientists, who are
looking for new options in formulating challenging drug substances, to have confidence in
exploring polyvinyl alcohol.
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Chapter 3
New Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for
Poorly Water-soluble Drug Delivery (Part 2)
3.1 INTRODUCTION
One of the current challenges facing the pharmaceutical industry is addressing the
increasing presence of poorly water soluble drugs in commercial products and development
pipelines [2-4]. Using amorphous solid dispersions for oral delivery as a method to solve
these challenges has increased in popularity in both commercial products and industry
literature [1, 140-142]. For research purposes, itraconazole is often used as a model drug
for concentration enhancement due to its aqueous solubility of approximately 1 ng/ml at
neutral pH and approximately 4 µg/ml at 1.2 pH [41, 143, 144]. ITZ has been formulated
in various polymeric carriers including hydroxypropylmethylcellulose (HPMC) [87, 89],
copovidone (PVPVA) [94], polyethyleneglycols (PEG) [97], polymethacrylates [145],
hypromellose acetate succinate (HPMCAS) [146], hypromellose phthalate (HPMCP) [41],
Soluplus® [147], polyvinyl acetate phthalate (PVAP) and cellulose acetate phthalate (CAP)
[42].
The KinetiSol® Dispersing (KSD) technology is a thermal process than can create
solid amorphous systems from challenging drugs and very highly viscous polymers [71].
Utilizing this technology in our previous study, a broad range of molecular weights and
degrees of hydrolysis of polyvinyl alcohol (PVAL) were investigated as a primary carrier
in amorphous solid dispersion systems and for their solubility/bioavailability enhancing
effect on itraconazole. EMD Millipore’s PVAL was utilized in both studies and the
nomenclature for describing different polymer grades is X-Y. X represents the viscosity
(in mPa·s) of the 4% aqueous solution at 20 °C, which is a relative indication of the molar
mass and Y is the degree of hydrolysis of the polyvinyl acetate. An examination of the
72
effects of molecular weight were conducted using PVAL 4-88, 26-88 and 40-88 with the
4-88 grade performing the best both from a KinetiSol® processing and dissolution
enhancement point of view. Subsequently, 4-38, 4-75, 4-88 and 4-98 grades of PVAL
were tested to ascertain the effect of the degree of hydrolysis for dissolution performance
of ITZ. PVAL 4-38 did not fully release due to the fact that polyvinyl acetate, the
predominant component of the grade, is less water soluble than PVAL. PVAL 4-98 also
did not fully release due to the highly crystalline nature of the fully hydrolyzed grade which
swelled in the aqueous environment, but did not completely dissolve. Both PVAL 4-75
and 4-88 released fully in the acidic portion of the dissolution test, but after the pH change
to the neutral media the 4-88 grade provided best maintenance of supersaturated drug
concentrations.
Research conducted on various molecular weights of HPMC on the dissolution
performance of ITZ show that higher molecular weights are more efficient stabilizers of
drug supersaturation after the pH change from the acidic gastric condition to the neutral
intestinal environment [41, 132]. Similar to HPMC, PVAL has a wide spectrum of
molecular mass from low to high viscosity ranges and it is anticipated that it will have an
effect on the performance of the amorphous dispersion. Previous experimentation of
PVAL 26-88 and 40-88 showed that these grades are excessively viscous as to pose
processing challenges, which resulted in uneven drug distribution within the polymer.
However, there are several grades between 4-88 and 26-88, namely 5-88, 8-88, 18-88 and
23-88, which could be investigated to determine if molecular weight effects post pH change
dissolution performance. The current research comparatively evaluated the PVAL grades
within a processable viscosity range (4-88 to 18-88) for their effect on the properties of
amorphous dispersions of ITZ prepared by KSD.
73
Rendering a drug amorphous within a semi-crystalline polymeric carrier does raise
concerns for the long term storage stability of the formulation [148-150]. Since the drug
thermodynamically prefers the crystalline state, the polymeric carrier must prevent this
occurrence through steric hindrance or molecular interaction. The concern of semi-
crystalline polymers is that structured molecular geometry either allows for the formation
of polymer rich and drug rich domains or that the crystalline geometry negatively
influences the unstable amorphous drug. This is due to the stronger polymer-polymer
interactions with semi-crystalline polymers (compared to amorphous ones) and hence the
drug must compete with the polymer itself for binding sites on the formation and on the
storage of the dispersion. PVAL does have at least one advantage over other semi-
crystalline polymers like polyethylene glycol (PEG) in that it does have a higher Tg and
Tm, which results in lower molecular mobility at temperature ranges associated with
physical stability.
PVAL is known for providing solution stabilization as it is used in the
pharmaceutical industry both as a stabilizing agent for emulsions [110] and as an emulsifier
in creating PLGA nanoparticles [117, 118]. The previous research illustrated in both in
vivo and in vitro studies PVAL’s ability to increase free drug concentrations, and
consequently oral absorption of the small molecule, itraconazole. Because of this
performance, it is hypothesized that an in solution interaction exists between ITZ and
PVAL and can be characterized. In an attempt to determine the mechanism of interaction
that allows this apparent solubility increase, the current study employed the analytical tools
of Fourier transform infrared spectroscopy (FTIR) and dissolution-ordered spectroscopy
(DOSY).
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3.2 MATERIALS
Itraconazole was purchased from Neuland Laboratories Limited (India). All grades
of PVAL (EMD Millipore) were donated by Merck Millipore. All other chemicals used in
this study were ACS grade
3.3 METHODS
3.3.1 KinetiSol® Dispersing (KSD)
Compositions for this study were produced by a lab scale, GMP pharmaceutical
compounder designed and manufactured by DisperSol Technologies, L.L.C. (Georgetown,
TX, USA). Prior to KSD processing, materials were weighed, dispensed into a
polyethylene bag, manually shaken for approximately 1 minute, and charged into the
compounder chamber. During processing, computer controls monitor processing
parameters in real time and eject the material at a pre-set ejection temperature. Discharged
material was immediately quenched in a cooling die under pressure in a pneumatic press.
Cooled material was then cryomilled in a SPEX 6870 Freezer/Mill, with a 2 cycle run of 5
minutes each at 10 cycles per second after a 3 minute cool time and 2 minute timer between
cycles. All further analyses was conducted on this powder.
3.3.2 Powder X-Ray Diffraction (XRD)
An Inel Equinox 100 X-ray diffractometer (INEL, Artenay, France) was used to
detect the presence of ITZ crystallinity. Milled compositions, physical mixtures and
unprocessed, pure ITZ were individually loaded on a rotating aluminum sample holder and
placed in the radiation chamber. The Equinox 100 utilizes Cu K Alpha radiation (λ =
1.5418 Å) with a curved radius detector to simultaneously measure a 2ϴ range of 5 - 110°.
Operating voltage and amperage were adjusted to 41 kV and 0.8 mA respectively and the
scan time for each sample was 10 minutes.
75
3.3.3 Polarized Light Microscopy (PLM)
PLM analysis was conducted on a Meiji Techno MT 9300 polarizing light
microscope with a first order red compensator. Pulverized samples were dusted on a glass
slide and viewed under 400x magnification. The slide holder was rotated at least 90
degrees while being observed to detect any light refractions.
3.3.4 High Performance Liquid Chromatography (HPLC)
The ITZ content in processed samples and dissolution aliquots were analyzed with
a Dionex Ultimate 3000 H/UPLC system equipped with diode array detector extracting at
263 nm. The system was operated under isocratic conditions with a 70:30:0.05
acetonitrile:water:diethanolamine mobile phase at a flow rate of 1.0 mL/min. The column
used for analysis was a Phenomenex Luna 5 µm C18(2) 100 Å, 150 mm x 4.6 mm
(Phenomenex, Torrance, CA, USA) HPLC column. Dionex Chromeleon 7.2 software was
used to analyze all chromatography data.
3.3.5 Non-Sink Dissolution Analysis
Non-sink dissolution analysis was conducted with a VK 7000 dissolution tester
(Varian, Inc., Palo Alto, CA, USA) configured as Apparatus 2. The test was performed
similar to USP XXXVII (38) dissolution for delayed release dosage forms. Solid
dispersions (n=3) were weighed to achieve a mass equivalent to 37.5 mg ITZ and dispensed
in dissolution vessels on the surface of 750 ml of 0.1 N HCl (~10x ITZ equilibrium
solubility in acid) equilibrated to a temperature of 37.0 ± 1 °C with a paddle rotation of 50
rpm. After 2 hours, a buffer medium of 250 mL of 0.2M Na3PO4, preheated to 37.0 ± 1
°C, was added to the dissolution vessels to adjust the pH to 6.80.
Drug content in solution was directly measured with a fiber optic Spectra™
instrument (Pion Inc., Billerica, MA, USA) fitted with 5 mm path length Pion Probes.
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Readings were recorded every 5 minutes over the entire duration. Additionally, samples
were taken at 2:00, 2:05, 2:10, 2:15, 2:30, 3:00, 3:30, 4:00 and 5:00 hours. Samples were
immediately filtered using 0.2 µm PVDF with GMF membrane, 13 mm filters, diluted at a
1:1 ratio with mobile phase, mixed and then transferred into 1.5 mL vials for HPLC
analysis. Pion data was correlated to match HPLC results by selecting appropriate 2nd
derivative parameters.
3.3.6 Precipitation Inhibition Analysis
Solid dispersions (n=3) were weighed to achieve an equivalent of 37.5 mg ITZ and
placed in suitable vessels containing 750 ml of 0.1 N HCl (to match concentrations in non-
sink dissolution studies) that had been equilibrated to a temperature of 37.0 ± 1 °C.
Containers were placed on stirring tables and agitated vigorously for several hours until
solutions became clear. Media was then transferred to dissolution vessels within a VK
7000 dissolution tester (Varian, Inc., Palo Alto, CA, USA) configured as Apparatus 2 with
a paddle rotation of 50 rpm. A buffer medium of 250 mL of 0.2M Na3PO4, preheated to
37.0 ± 1 °C, was added to the dissolution vessels to adjust the pH to 6.80. Samples were
taken immediately before pH change, then after the pH change at 5, 10, 15, 30, 60, 90, 120,
and 180 minutes. Samples were immediately filtered using 0.2 µm PVDF with GMF
membrane, 13 mm filters, diluted to a 1:1 ratio with mobile phase, mixed and then
transferred into 1.5 mL vials for HPLC analysis.
3.3.7 Fourier Transform Infrared Spectroscopy (FTIR)
Samples were tested in a Thermo Scientific Nicolet iS50 FT-IR Spectrometer
(Thermo Electron Scientific Instruments LLC, Madison, WI, USA) with the Omni-
Sampler module for attenuated total reflectance (ATR). The scan range was 2000 – 700
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wavenumber (cm-1) at a resolution of 4 cm-1 for 32 scans per sample. Data collection and
analysis were performed with OMNIC™.
3.3.8 Diffusion-Ordered Spectroscopy (DOSY)
Amorphous dispersions and PVAL were dissolved in deuterated solutions of 0.1N
DCl prepared by diluting concentrated DCL with D2O. Samples were tested in a Varian
VNMRS 600MHz nuclear magnetic resonance (NMR) spectrometer (Palo Alto, CA, USA)
for solution with a Doneshot pulse sequence. The spectra was adjusted until water at 25
°C was 19.02 x 10-10 and all data generated is correlated to that reference. Figures were
generated using Varian VNMRJ software.
78
3.4 RESULTS AND DISCUSSION
3.4.1 Evaluation of PVAL Molecular Weight
To be consistent with our previous study, a drug loading of 20% ITZ was selected
for the preparation of amorphous dispersions with PVAL grades of 4-88, 5-88, 8-88 and
18-88. All acceptable KSD compositions were verified to be amorphous by XRD and
PLM, and HPLC analysis was conducted to establish dispersion potencies (data not
shown). For dissolution testing, the samples were weight adjusted according to potency to
achieve an equivalent amount of ITZ in each vessel. Figure 3.1 contains the dissolution
curves of the listed PVAL grades for the 2 hour pH change dissolution method. Error bars
are not shown due to data density making them indistinguishable.
Figure 3.1: Dissolution profiles of 20% ITZ in PVAL 4-88, 5-88, 8-88 and 18-88.
Both PVAL 4-88 and 5-88 grades fully released ITZ at supersaturated levels with
little variance between the two in the acid phase. PVAL 8-88 and 18-88 were not able to
79
achieve complete release, which was observed during the test with powder appearing at the
bottom of the dissolution vessels after approximately an hour. After the pH change the
precipitation inhibition performance followed the reverse order of molecular weights: 4-88
> 5-88 > 8-88 > 18-88.
Prior to the pH change, 8-88 had only reached 70% of drug in solution and 18-88
had only attained 60%. It was speculated that if these two grades could achieve 100% drug
release the rank order of performance might change. An alternative dissolution study using
the same amorphous dispersions, called precipitation inhibition analysis, was conducted
which forced complete drug release from all polymer grades prior to the pH change with
the results exhibited in Figure 3.2.
Figure 3.2: Precipitation inhibition curves of 20% ITZ in PVAL 4-88, 5-88, 8-88 and
18-88.
Even with the formulations at the same starting point, the lower molecular weights
outperformed the larger ones in reducing the rate of drug precipitation. These results match
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the previous study where PVAL 4-88 provided better performance than combinations
containing the 26-88 and 40-88 grades. Thus, contrary to the trends observed with HPMC,
for PVAL the lower molecular weights have superior dissolution performance over higher
molecular weights.
This trend is confirmed by comparing the rates of dissolution for the polymers
themselves in water. Product literature shows that lower molecular weights of the -88
grades have faster dissolution rates specifically in the temperature range between 20 and
40 °C [109]. Additionally, as shown in that same product literature, PVAL reduces
interfacial tension, particularly the surface tension of water with respect to air, with
differing effects according to molecular weight as seen in Figure 24. That figure
specifically compares PVAL grades 40-88, 18-88, 8-88 and 4-88 for reduction in water
surface tension. The rank order of greatest surface tension reduction to lowest is 4-88 > 8-
88 > 18-88 > 40-88. Thus, the lower molecular weights have a greater reduction in surface
tension of water.
Since amorphous dispersion powders were dispensed on the surface of the media
in the vessels for the non-sink dissolution test, the lower surface tension and faster
dissolution rate of the lower molecular weight grades would speak to the faster dissolution
rate of ITZ. The effect on water surface tension indicates that lower molecular weight
grades effectively function as a polymeric surfactant more than higher molecular weights.
This would support the results for the precipitation inhibition analysis where the lower
molecular weights were more effective in reducing the rate of drug precipitation.
3.4.2 Drug Loading Evaluation
All dissolution studies from the current and previous research have been conducted
with 20% drug loading. It is noted that the drug loading of ITZ:HPMC in the commercial
81
product Onmel™ and the coating for the nonpareil beads in Sporanox® which is also ITZ
in HPMC are both 40% [139]. Typically, the higher the drug load, the lower the dissolution
performance because the ratio of drug to polymer decreases and solubility enhancement
trends with increasing polymer concentration [151]. However, if higher drug loading can
be achieved, the size of the dosage form can be reduced, typically improving patient
convenience and compliance. Hence, optimal drug loading is a balance between
performance and size of the final dosage form.
To investigate the effect of drug loading on dissolution performance, amorphous
dispersions of ITZ in PVAL 4-88 were produced at 10, 20, 30, 40 and 50% drug loads.
HPLC analysis measured actual potencies and samples were weight adjusted to ensure 37.5
mg of drug were contained in each dissolution vessel. The result from the non-sink
dissolution test is found in Figure 3.3.
Figure 3.3: Dissolution comparison of different ITZ loadings in PVAL 4-88.
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The rank order from highest dissolution performance in acid is as follows: 20% >
30% > 40% > 10% > 50%. Surprisingly, the 10% dispersion did not have the highest rate
of dissolution. It exhibited a faster initial rate than 30% and 40%, but slowed after the
initial 20 minutes to perform only better than the 50% loading. Only the 10% and 50%
drug loading did not achieve 100% drug release within the two hour window of the acid
portion of the experiment.
Toward the end of the 2 hour acid phase of the dissolution test, powder was visible
at the bottom of the vessel of the 50% composition. All other vessels were clear at the
bottom, however there was still powder floating at the top of the vessel of the 10% drug
load sample. Keeping the relative amounts in perspective can provide probable
explanations for this behavior. The 10% drug loading has a theoretical weight of 375 mg,
the 20% drug loading has 187.5 mg weight on down to the 50% drug loading only having
75 mg of total amorphous intermediate powder. The 187.5 mg of 20% ITZ loaded powder
floated on top (like all other samples) initially, then within a few minutes dispersed into
the vessel and was dissolved within 20 minutes. Both the 30% and 40% loaded samples
followed the same pattern, but with longer timeframes. In the case of the 10% ITZ
dispersion, the time for the floating material to disperse within the aqueous environment
and then dissolve was so prolonged that a very small amount of powder remained on the
top surface at the end of the 2 hour acid phase. Visually, it was only a fraction of the initial
375 mg amount but it is unclear as to whether it could account for all of the undissolved
amount of ITZ.
Results from the previous study and product literature show that increasing polymer
crystallinity reduces polymer solubility and dissolution rate. The lowest drug loading at
10% would have the highest allowance for the formation, in some regions, for the preferred
crystalline configuration which would slow dissolution and negatively affect solubility.
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With the more crystalline configuration, ITZ could be entombed in highly crystalline
regions which would account for the incomplete release and the more sustained drug
solubility after the pH change due to higher polymer concentrations. Increasing drug load
would decrease polymer crystallinity and allow for the faster dissolution for the 20%
sample. However, increasing the drug loading also increases the hydrophobicity of the
dispersion resulting in slower wetting and dissolution as seen with the 30% and 40%. The
50% dispersion would have the lowest polymer crystallization, but also the most reduced
wetting and diminished release rate due to low polymer concentration.
After the pH change the rank order follows as was expected with 10% > 20% >
30% > 40% > 50%. 10% ITZ did start at a lower concentration than the 20%, but had
higher actual amounts of drug in solution at 180 minutes which was an hour after the pH
change. The 20% ITZ composition had the fastest dissolution rate and reduced the rate of
precipitation at a similar level to the 10% composition. The 30% loading was a close
second to 20% in the acid phase dissolution and exhibited a rate of precipitation only
slightly lower than both the 10% and 20% compositions. Since, optimal drug loading is a
balance between performance and size of the final dosage form, the 30% loading is
probably closer to the optimal drug loading than all the other drug loadings tested.
3.4.3 Evaluation of the ITZ/PVAL Interaction
Because the ITZ is amorphous in the solid dispersion, it is not surprising to see
apparent solubility levels much higher than the crystalline equilibrium solubility.
However, without the aid of a solubility enhancing/stabilizing polymer, the
thermodynamically unstable supersaturation would soon return to the crystalline
equilibrium solubility. Especially, as the aqueous environment transitions from the acid
gastric environment to the pH neutral environment of the intestinal tract, a weakly basic
84
drug like ITZ would return to solubility equilibrium quite rapidly [132]. Dissolution
profiles contained in this and the previous study report concentration levels as high as 8,000
times the saturation concentration in neutral media and maintaining at least 4,000 times the
saturation concentration for 30 minutes after the pH change. These results suggest an
attractive interaction between the ITZ and PVAL.
FTIR-ATR has been reported as an analytical tool to investigate such possible
interactions [53, 152, 153]. Peaks in the spectra can be associated with specific atomic
bonding and shifting or changing shape can indicate molecular interactions. Figure 3.4
contains the FTIR spectra of amorphous itraconazole, preprocessed PVAL 4-88 and
amorphous solid dispersions of 10% and 20% ITZ loading in PVAL 4-88.
Figure 3.4: FTIR-ATR spectra of amorphous ITZ, PVAL 4-88, and amorphous
dispersions.
85
The result for ITZ is similar to published literature [154, 155] and the PVAL result
is consistent with product literature [109]. For PVAL, the broad peak at 3330 cm-1 is
associated with O-H stretching, the small peak at 2941 cm-1 with C-H stretching, the 1732
cm-1 peak with C=O groups (from unhydrolyzed ester groups), the peak at 1429 cm-1 with
CH2 bending, the 1251 cm-1 peak with the C-O-C groups (also from unhydrolyzed ester
groups) and, finally, the 1093 cm-1 peak is associated with C-O stretch and O-H bending.
For ITZ, the first major peak at 1700 cm-1 is associated with C=O stretching, the 1511 cm-
1 peak is related with CO-NH2, and the 946 cm-1 linked with C-Cl. Most peaks do not show
any difference between the individual components and the amorphous dispersions. Yet,
the broad peak associated with O-H stretching on PVAL showed a shift from 3330 cm-1 to
3334 and 3335 cm-1 on the 10% and 20% ITZ loading in PVAL 4-88 respectively. The
ITZ peak at 1700 cm-1 that correlates to C=O stretching, shows a change of 1713 and 1706
cm-1 for the same respective 10% and 20% ITZ loaded amorphous dispersions. As
mentioned previously, the 10% amorphous dispersion will exhibit a higher degree of
polymer crystal formation than the 20% load, which might explain the larger shift for the
lower drug load. While it does appear that hydrogen bonding might be occurring, the
magnitude of the shifts advocates that interactions, more than just hydrogen bonding alone,
would account for the storage stability of the amorphous dispersion.
Diffusion-ordered spectroscopy (DOSY) or sometimes called diffusion-ordered
NMR spectroscopy and diffusion-ordered correlation spectroscopy has been used to
determine the drug complexation with cyclodextrins [156], drug release from a hydrogel
matrix [157], identification of fake formulations of commercial products [158], and to see
the interactions of polymers and drugs in solution [159]. DOSY is a measure of diffusion
and can distinguish different components in a formulation by the rate of diffusion and
location on the spectra. Small molecules have a faster diffusion rate than large polymers
86
and will have a different measurement of diffusion unless they are strongly bound by a
covalent, ionic or hydrogen bond, which would give them the same measurement of
diffusion as they act as single entity. Figure 3.5 has the DOSY map for PVAL 4-88 only
and for the 20% drug loading in PVAL4-88.
Figure 3.5: DOSY maps of (A) PVAL 4-88 and (B) 20% ITZ in PVAL 4-88 amorphous
dispersion.
The Y or F1 axis is the measurement of diffusion or how well the molecules travel
within the solution with lower numbers at the top representing slower diffusion and
increasing with the numbers to reach the highest diffusion rates at the bottom. The X or
F2 axis helps track any chemical shift from the top spectra. Figure 3.5A is a map of pure
PVAL 4-88 that has not been processed. It is interesting to note that the polymer has two
different diffusion coefficients, with the first band around 0.4 and the second one around
A B
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1.0 on the F1 axis. Product literature speaks specifically about PVAL’s propensity toward
complex formation in the presence of certain acids or salts [109]. Since the solution is
0.1N DCl, it is possible to have PVAL form a bimolecular complex. Additionally, in the
discussion regarding PVAL reduction of water surface tension, it was mentioned that
PVAL 4-88’s greater effect on surface tension would allow it to function with surfactant-
like properties, which would allow for molecules to self-associate in solution. Thus, it
appears that the two different diffusion coefficients is formed by some molecules going
into solution in groups and other by themselves. Whatever the actual cause is for the
grouping phenomena, it appears that acetate groups on the PVAL molecular chain play a
part because the spectra associated with acetate (around 2 on the F2 axis) is only observed
in the slower diffusion group. Also on Figure 3.5A is an area that is around 10 on the F1
axis and around 2 on the F2 axis; this charts the residual acetyl groups within the bulk
polymer.
Figure 3.5B is a map of the amorphous dispersion containing 20% ITZ in PVAL4-
88. At the top, again, is the two different diffusion coefficients of the PVAL 4-88. Around
3 on the F1 axis is the spectra of itraconazole, which illustrates a different measurement of
diffusion for the drug than the polymer. This illustrates clearly that the drug is not tightly
bound to the polymer by strong intermolecular interactions. If there is any hydrogen
bonding, the drug/polymer association would have to be flexible enough to allow ITZ
movement along PVAL to account for the different rates of diffusion. Ideally, a third
DOSY map of only ITZ in solution would be very useful to see if the interaction of the
polymer changes the diffusion for the drug to illustrate a practical interaction between the
two, but, unfortunately, the concentration of ITZ in solution was below the limit of
detection for this analytical test. There is an area around 2 on the F1 axis that lies between
the diffusion of PVAL 4-88 and ITZ that could possibly be a slower measured diffusion
88
for ITZ that would indicate an interaction. However, it could also be a software
interpretation error due to peaks of both PVAL 4-88 and ITZ both occurring in that area.
Thus, the key conclusion that can be drawn from these results is that the concentration
enhancing effect of PVAL on ITZ is likely the result of weak intermolecular interactions,
such as van der Waals forces/hydrophobic interactions, as it appears that strong
intermolecular interactions between ITZ and PVAL do not occur in solution. This
conclusion is supported by other research efforts that have looked at amorphous dispersions
of ITZ with various polymeric carriers and concluded that hydrogen bonding was not the
mechanism of action in solution between the drug and polymer [42, 132].
3.4.4 Evaluation of Stability
One of the main concerns to be addressed when creating amorphous dispersions is
the stability of the matrix to prevent the drug from returning to its crystalline state within
the delivery form before dosage [54, 57, 160]. Physical stability of the drug substance can
be achieved through kinetic stabilization or freezing the amorphous drug within the
polymeric carrier. This can be achieved by having a Tg of the composite matrix 50 °C
above ambient storage conditions [52]. It can also be achieved by thermodynamic stability
which is attained by molecular interactions that provide stability [56]. Many amorphous
dispersions are formulated in a metastable region where the mode of stabilization is a
combination of both kinetic and thermodynamic mechanisms [57]. Drug loading also
influences stability because as loading is increased, at some point miscibility is exceeded
and then drug molecule proximity within the polymer matrix becomes critical. Stability
tends to decrease because recrystallization becomes more probable as drug molecules are
increasingly found in close proximately to other drug molecules.
89
The drug loading portion of the current study concluded that 30% ITZ in PVAL 4-
88 is probably closer to the optimal drug loading than all the other drug loadings tested. A
container (without desiccant) containing milled amorphous intermediate powder of 30%
ITZ was stored at ambient conditions for 30 months. A new sample that was identical in
formulation was prepared and compared to the 30-month-old material by XRD and PLM.
The XRD diffractogram is shown in Figure 3.6.
Figure 3.6: XRD profiles of ITZ, initial and 30 month old amorphous dispersions.
Both the initial and 30 month XRD profiles contain no peaks that correspond with
ITZ indicating that both are substantially amorphous. The major broad peak in the
amorphous dispersions at approximately 19 2-theta and minor peaks at approximately 23
and 41 2-theta are related to the crystallinity of the PVAL 4-88. No visual crystal structures
were observed in either samples by PLM. Since it is possible to have crystals below the
limit of detection of XRD and PLM, a dissolution study was conducted to confirm the
dissolution performance of the amorphous compositions. These results are presented in
Figure 3.7. As stated in the methods section, the first 120 minutes of the dissolution was
90
performed in 0.1 N HCL after which a buffer is added to change to a neutral pH. Thus, in
the acidic environment full release of ITZ is realized after which the pH change resulted in
precipitation of ITZ. Since only two dissolution profiles are compared in this figure, error
bars were included to show the significance of any variation.
Figure 3.7: pH change dissolution comparing initial and 30 month ambient storage
amorphous dispersions of ITZ:PVAL 4-88 (30% drug loading).
The dissolution performance in 0.1 N HCl of the two compositions are comparable
with the 30 month old composition performing slightly better. Two different lots of PVAL
4-88 were used to make these compositions, which could explain the slight variance.
Another possibility is that the stored material had some water absorption that would allow
for better wetting and faster release. Since the purpose of the test was to determine crystal
growth during storage, the reason for this variance was not investigated. After the pH
change, the two compositions performed similarly with the two curves staying within the
error bars. Because the dissolution performance is similar, it can be concluded that the
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solid-state properties of ITZ in the PVAL matrix did not change during storage. Therefore,
dissolution performance and XRD results demonstrate acceptable real-time ambient
stability for the lead ITZ:PVAL 4-88 composition.
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3.5 CONCLUSION
PVAL has been further investigated as a solubility enhancing polymer in
amorphous solid dispersions as enabled by KinetiSol® Dispersing. PVAL 4-88 was
confirmed to provide the best solubility enhancement and in solution stability as compared
with 5-88, 8-88 and 18-88 presenting a trend that lower molecular weights function better
than higher molecular weight polyvinyl alcohols. In a drug loading study, 20, 30 and 40%
ITZ drug loads achieve full drug release in 0.1 N HCl in 2 hours, and were able to retard
the return to the crystalline equilibrium solubility after the pH change in the expected rank
order of 10%>20%>30%>40%>50% with the 30% loading selected as optimal. DOSY
and FTIR were used confirm that weak molecular interactions are the likely cause of solid
state and solution stability of amorphous ITZ. A 30 month stability study showed the
optimal ITZ:PVAL 4-88 amorphous dispersion remained entirely amorphous as
determined by XRD and PLM and the dissolution performance was unchanged.
93
Chapter 4
Novel formulation approach for multiparticulate abuse deterrent
development
4.1 INTRODUCTION
The misuse and abuse of prescription drugs poses a serious public threat in the
United States today. The Centers for Disease Control and Prevention (CDC) have declared
that the United States is in the midst of an epidemic of prescription drug overdose deaths
[161]. The CDC reported that drug overdose deaths were second only to motor vehicle
crash deaths among the leading causes of unintentional injury death in 2007 [162]. That
same report issued statistics that the number of deaths involving opioid analgesics was 1.93
times the number involving cocaine and 5.38 times the number involving heroin. A 2010
Substance Abuse and Mental Health Services Administration survey found that 16 million
Americans age 12 years and older had taken a prescription pain reliever, tranquilizer,
stimulant, or sedative for nonmedical purposes at least once in the previous year; 7 million
had used psychotherapeutic drugs nonmedically within the past month. Of these drug
abusers, 55% said they obtained the drug they most recently used from a friend or relative
for free [163]. These statistics express the rising need for drug formulators and regulators
to create barriers to prescription drug abuse.
To combat this growing epidemic, the U.S. Food and Drug Administration has
released a guidance document for drug formulation companies to follow for formulating
prescription drugs prone to abuse [164]. That guidance document offers several suggested
approaches that are summarized in Table 4.1.
94
Approach Brief Description
Physical/chemical
barriers
Physical barriers can prevent chewing, crushing, cutting,
grating or grinding of the dosage form. Chemical barriers
can resist extraction of the drug using common solvents like
water or organic solvents.
Agonist/antagonist
combinations
A drug antagonist can be added to interfere with, reduce or
defeat the euphoria associated with abuse.
Aversion Substances can be added to the product to produce an
unpleasant effect if the dosage form is manipulated or is used
at a higher dose than directed.
Delivery system Certain drug release designs or method of delivery can offer
resistance to abuse like a sustained-release subcutaneous
implant.
New molecular entities
and Prodrugs
The properties of a NME or prodrug could include the need
for enzymatic activation, different receptor binding profiles,
slower central nervous system penetration or other effects.
Combination Two or more of the above methods could be combined to
deter abuse.
Novel approaches This category encompasses novel approaches that are not
captured in the previous categories.
Table 4.1: Categories for abuse deterrence as defined by the U.S. FDA.
The first category, physical and chemical barriers, represent the most prevalent
approach in currently available commercial products. The most financially successful
commercial abuse deterrent formulation has been Purdue Pharma’s OxyContin®, which
95
was reformulated in a polyethylene oxide matrix as a physical barrier and approved by the
FDA in April 2010 [165, 166]. The original product label did not contain any information
on abuse deterrence despite having in vitro evidence to support such a claim. After product
launch several studies investigated the public health impact of the OxyContin®
reformulation to support the relabeling of the product with abuse deterrent information.
One study looked at patients entering treatment programs with opioid dependency [167].
The selection of OxyContin® as a primary drug of abuse decreased from 35.6% of
respondents before the release of the abuse-deterrent formulation to just 12.8% 21 months
later. Those same respondents reported that of all opioids used to ‘get high in the past 30
days’ OxyContin® fell about 40% while the use of heroin nearly doubled over the same
time period. Another study reported that abuse of the reformulated OxyContin® was 41%
lower than historic abuse of the original formulation [168]. ‘Real world’ in vitro testing
demonstrated the relative difficulty of manipulation of the reformulation [169] along with
human in vivo testing [170] assessed the actual abuse deterrent properties of the
reformulation. While not completely tamper proof, the reformation of OxyContin® did
prove to be a deterrent in all evaluations.
The use of a polyethylene oxide (PEO) matrix has been utilized in Opana® (an
oxymorphone reformulation by Endo Pharmaceuticals) and in Nucynta® (a tapentadol
reformulation by Ortho-McNiell-Janssen Pharmaceuticals) but neither have been allowed
to state abuse deterrence on product labels by the FDA even with some post-marketing
studies [166]. Remoxy® (Pain Therapeutics, Inc.) is an oxycodone extended release
product that does not use PEO to provide a physical barrier but rather a formulation
containing sucrose acetate isobutyrate in a gelatin capsule [171]. The formulation creates
a viscous mass that resists size reduction even when frozen and only releases a fraction of
the oxycodone when submerged in high-proof alcohol for hours. Clinical trials showed
96
significant pain reduction and survey data from drug counselors demonstrated that it was
less preferred for abuse as compared to the original ER oxycodone formulation [172, 173].
However, the FDA issued a complete response letter in June, 2011, indicating additional
studies were required before approval would be granted. Since sucrose acetate isobutyrate
is not considered GRAS by the FDA, there appears to be an opportunity for creating a solid
matrix product out of GRAS excipients that does not contain PEO as a barrier approach in
abuse deterrent formulation.
There are commercial products that belong to other abuse deterrent categories.
Suboxone® is categorized as an agonist/antagonist combination of buprenorphine and
naloxone, where the buprenorphine acts as a partial opioid agonist combined with the
opioid agonist naloxone. It was approved in 2003 by the FDA for the treatment of opioid
dependence but is commonly used off-label as a pain therapeutic [174]. Embeda® is also
an agonist/antagonist combination of morphine and naltrexone. When taken orally as
intended, the naltrexone is not released. But, if the tablet is chewed or crushed prior to
taken orally, the naltrexone is released with the morphine and the agonist activity is limited
[175]. This complex formulation encountered manufacturing issues and was recalled in
March, 2011. Oxecta® is an immediate release formulation of oxycodone that contains
aversive ingredients. Since the active ingredient is readily available via the oral route, the
aversion abuse deterrent approach is to reduce non-oral abuse. The formulation contains
sodium lauryl sulfate which irritates the nasal cavity to deter insufflation and it also
contains excipients that form a gel when exposed to water to deter intravenous use [176].
Dysphagia, or difficulty in swallowing tablets, greatly influences patient
compliance. A study has shown that up to ¼ of the general population may have problem
swallowing, with the very young having the most difficulty followed by elderly patients
[177]. Unfortunately, these age groups are commonly issued prescriptions for drugs that
97
are likely to be abused. For example, in 2007, 3.1 million youths aged 12 to 17 received
treatment or counseling for problems with behavior or emotions with a significant
percentage receiving psychotherapeutic drugs [178]. On the other hand, different studies
have shown that the age group most likely to suffer from chronic pain is age 50 to 64 [179,
180]. It would be highly beneficial to have a delivery form that could simultaneously
provide ease of dosing for patent compliance while at the same time delivering abuse
deterrence.
One such approach would be to have a physical barrier formulation in a
multiparticulate delivery form rather than a single, larger abuse deterrent tablet. The
smaller particles would allow for oral delivery by sprinkling onto soft food for consumption
to help with patient who suffer with dysphagia. In addition to ease of dosing, there are
other biopharmaceutical advantages with having a multiparticulate delivery form.
Gastrointestinal tract (GIT) transit time for small particles would not depend upon gastric
emptying, which would result in a more uniform distribution in the GIT and less variable
pharmacokinetic profiles among patients. However, the challenge with a multiparticulate
approach is that the smaller particle size has higher susceptibility to certain mechanical
abuse techniques such as size reduction by a coffee grinder or mortar and pestle. The high
surface area also lends faster drug release when submerged in ethanol, which is also a
common abuse technique. So, while the theory of a multiparticulate delivery is appealing,
the technical details to the approach are challenging.
Currently, the most published multiparticulate approach is a platform technology
called DETERx (Collegium Pharmaceuticals, Inc.) that creates a complex of drug with
fatty acid and then places it with a hydrophobic waxy matrix in submillimeter, spherical
particles for extended release [181-183]. The spherical particles are prepared using a
standard spray congealing process and are specifically designed to retain the time-release
98
mechanism following common methods of tampering (e.g. crushing, chewing, heating for
IV injection, etc.). The release profile can be adjusted by excipient ratios and particle size.
Not much information is available on the challenge of creating the drug/fatty acid ionic
complex, but a simple drug-in-a-matrix approach would be less complex and would
possibly allow for a broader range of drugs to be incorporated in the platform.
The KinetiSol® Dispersing (KSD) technology is a thermal process than can create
solid amorphous systems from challenging drugs and very highly viscous polymers [71].
While most publications on this technology deal with amorphous systems, the process can
produce dispersions of crystalline drug just as straightforward as amorphous ones.
Polymers with viscosity too large for process via extrusion have been successfully
processed with KSD with the resulting solid systems being very difficult to mill once
cooled [132]. While there is more to abuse deterrent systems than being difficult to mill,
the viscous polymers do inherently provide resistance to crushing and powder formation.
Additionally, the flexibility of KSD for polymer selection will allow for formulating with
polymers that have inherent ethanol resistance like using polyvinyl alcohol (PVAL). It is
hypothesized that through KSD, very viscous polymers like high molecular weight
hydroxypropylmethylcellulose (HPMC) can be combined with other excipients to create
abuse deterrent formulations. Furthermore, if combined with excipients that retard drug
release, very viscous polymers can be formed into a multiparticulate extended release
delivery form, providing dosing benefit to patients with dysphagia while not needing the
complex processing of DETERx.
99
4.2 MATERIALS
Theophylline (THEO) was purchased from Acros Organics (Thermo Fisher
Scientific). HPMC grades were received from Dow Chemical Company or purchased from
Ashland Chemical Company. Ethocel (EC) grades were also sourced from Dow Chemical
Company. TEC and DBS was purchased from Vertellus. EVAC and PVAL grades were
purchased from Sigma-Aldrich.
4.3 METHODS
4.3.1 KinetiSol® Dispersing (KSD)
Compositions for this study were produced by a lab scale, GMP pharmaceutical
compounder designed and manufactured by DisperSol Technologies, L.L.C. (Georgetown,
TX, USA). Prior to KSD processing, materials were weighed, dispensed into a
polyethylene bag, manually blended for approximately 1 minute, and charged into the
compounder chamber. For compositions with liquid components, the non-liquid
components were weighed and placed into a food processor. The liquid components were
then weighed out in syringes that had been tared after being flushed with the liquid
component (to compensate for the weight of residual liquid in the syringe after injection).
The liquid was slowly added to the non-liquid components and then mixed on low setting
for 2 minutes. During processing in the compounder, computer controls monitor
processing parameters in real time and eject the material at a pre-set ejection temperature.
Discharged material was immediately quenched in a cooling die under pressure in a
pneumatic press. Cooled material was then milled in a FitzMill L1A with a 0.156 inch
(approximately 5 mesh) screen after which particles smaller than a 12 mesh screen size
were removed from the resulting material. Formulations with high impact resistance
required cooling with liquid nitrogen prior to milling.
100
4.3.2 Non-Sink Dissolution Analysis
Non-sink dissolution analysis was conducted with a VK 7000 dissolution tester
(Varian, Inc., Palo Alto, CA, USA) configured as Apparatus 2. Samples equivalent to 37.5
mg THEO were weighed and added to the surface dissolution vessels filled with 750 ml of
0.1 N HCl equilibrated to a temperature of 37.0 ± 1 °C with a paddle rotation of 50 rpm.
Drug content in solution was directly measured at 270 nm with a fiber optic Spectra™
instrument (Pion Inc., Billerica, MA, USA) fitted with 5 mm path length Pion Probes.
Readings were recorded every 10 minutes for 24 hours. For dissolution containing ethanol,
300 ml of ethanol was added to 450 ml of 0.1 N HCl and equilibrated to a temperature of
37.0 ± 1 °C prior to adding samples.
4.3.3 Dart Impact Test
Dart impact tests were conducted on a custom made testing device. Essentially, a
dart (solid steel cylinder) weighing 1.198 kg is placed with in PVC tube that is mounted
vertically. A string and pulley system allows the dart to be raised to a specific height and
then released. At the base of the PVC tube is a flat steel plate where a tablet is placed to
be hit by the falling dart. The dart is raised to 213 cm in height so that the tablet is hit with
25 J of energy. A tablet passed the test if it remained intact in one piece without visual
cracks.
4.3.4 Coffee Grinder Size Reduction Test
Approximately one gram of the multiparticulates is weighed out and placed in a
KitchenAid coffee grinder. The coffee grinder is turned on for 15 seconds followed by a
15 second pause. This is repeated for a total time of 5 minutes. The ground material is
then placed on top of a screen stack containing 20, 40, 60, and 200 mesh with a pan at the
bottom to collect all fines that would pass through the 200 mesh. The screen stack was
101
mechanically shaken for two minutes. Each screen was weighted prior to sieving and then
weighted afterward to determine the total weight of material in each size range.
4.3.5 Syringeability Test
Approximately 500 mg of the multiparticulates were placed on a metal pan and held
over a propane torch set on the lowest setting. The height from the pan to the flame was
slowly reduced until the heat was sufficient to start melting the particle surfaces. Once
molten, the pan could be tipped so the melted material could pool on the lip of the pan and
be drawn up by a 20 gauge needle. The needle and syringe were pre-weighed so that any
material drawn up by the needled could be quantified by weighing the needle, syringe and
drawn material.
4.3.6 Water Extraction Test
Three 150 ml beakers were filled with 100 ml of distilled water and placed in three
different conditions. The first beaker was left at room temperature, the second one was
placed on a hot plate and brought to a mild boil, and the last one was placed in an ice water
bath to reach approximately 3 °C. Once the three beakers achieved the desired conditions,
25 mg of multiparticulate were placed in the water. Drug content in solution was directly
measured at 270 nm with a fiber optic Spectra™ instrument (Pion Inc., Billerica, MA,
USA) fitted with 5 mm path length Pion Probes. Readings were recorded every 2 minutes
for 3 hours. Test was concluded as soon as the water in the heated beaker reached a level
that would not allow for complete submersion of the fiber optic tip. The final volume was
measured and concentrations were calculated on the average of the beginning and final
volumes.
102
4.4 RESULTS AND DISCUSSION
4.4.1 Formulation Development
In the previous chapters and in other research [132] where amorphous solid
dispersions were created using high molecular weight polymers, it was discovered that
milling the KSD discharged material was a challenge. It was also discovered if the drug
was not rendered amorphous, then the discharged material was significantly easier to mill.
In general, it is known that drugs can function as plasticizers once they are rendered
amorphous or molten and it has been found that ITZ works well as a plasticizer in cellulosic
polymers [184]. Since drugs that are abused typically do not need bioavailability
enhancement, it would be preferred to make solid dispersion with drugs in their unaltered
or crystalline state. However, not only would the composition not gain the benefit of the
drug acting like a plasticizer, but the small, crystalline molecules would also have a
negative impact on mechanical properties of the polymer.
To compensate for this, a small component of the formulation must have some
plasticizing effect to retain impact properties sufficient to resist crushing or milling. A
screening study was conducted with 15 different excipients with HPMC E50 and 20%
THEO by processing the compositions by KSD and then directly forming a tablet for dart
impact testing. For confidentiality reasons, the 15 excipients will not be listed in this
chapter. Six of the formulations successfully passed the impact test; two of them were
selected to move forward with formulation development: triethyl citrate (TEC) and dibutyl
sebacate (DBS). TEC was selected because of the elastomeric properties that it imparted
on HPMC, which makes it particularly impact resistant. DBS was selected because it is
less water soluble than TEC and might provide a slower release in dissolution testing.
The desired release rate from an extended release delivery form is drug and therapy
dependent. In this study, THEO is being used as a surrogate for an opioid like oxycodone
103
because of its high melting point and water/alcohol solubility. For pain therapy, opioids
have been tested for in 4-6 hour and 12 hour release [185]. For a starting point, the authors
thought that a release profile around 6 hours could be representative of a target product
profile and was selected as the development goal. Several formulations were made from
the selected group of materials, HPMC, EC, PVAL, EVAC, TEC and DBS, and tested in
dissolution. Formulations that required at least 3 hours to achieve full drug in solution are
listed in Table 4.2. Along with the time to achieve full release, the table also contains an
impact rating, which was a subjective categorization after manually bending the discharged
after cooling in the compression mold. A rating of 1 was very easy to break, a rating of 2
required some effort to break, and a rating of 3 was very difficult or impossible to break.
Formulation Time to full
release
Impact
rating
62% HPMC E50 / 10% HPMC K100M / 8% TEC 3:00 3
44% PVAL 4-38 / 36% K100M 3:10 2
40% PVAL 4-88 / 40% PVAL 4-98 3:20 1
40% EVAC 12 / 30% HPMC K100M / 10% EC 10 4:00 1
40% EVAC 12 / 40% HPMC K100M 4:10 2
52% HPMC E50 / 10% EC 10 / 10% HPMC K100M / 8% TEC 4:10 2
42% HPMC E50 / 20% EC 10 / 10% HPMC K100M / 8% TEC 4:30 1
30% HPMC E15 / 30% HPMC K100M / 20% DBS 5:40 3
35% HPMC E15 / 35% HPMC K100M / 10% DBS 6:40 3
55% EC 10 / 25% DBS 35% in 24:00 1
80% EVAC 12 20% in 24:00 3
Table 4.2: Formulations tested to determine excipient trends (n=1).
Many of the formulations initially tested attained full release in around 2 hours, so
the formulation focus turned to determining combinations that released THEO very slowly.
EVAC is used for extended release transdermal drug delivery [186] and is used in the
plastic industry as an impact modifier [187]; consequently, it was not surprising that it
104
required more than 24 hours to release and received an impact rating of 3. EVAC was
introduced into formulations containing HPMC E50 and it did slow the release. But, the
time to full release was still faster than three hours and the impact rating of the
compositions were 2 or less. When combined with HPMC K100M, a release time of 4
hours was achieved but again the impact rating was 2 or less. Ethyl Cellulose is used in
formulations for extended release and lends itself well to thermal processing [188]. Mixed
with a high percentage of DBS yielded a composition that required more than 24 hours to
release. However, EC is brittle and very easy to grind or mill. It was added at 10 and 20%
in several formulations and generally aided in slow down release. Unfortunately, the
negative impact on the mechanical properties even at 10% was sufficient to make all
formulations a rating of 2 or less even with the impact augmenting effects of TEC.
HPMC K100M in combination with both plasticizers proved to be the best
mechanical property enhancing approach in formulation development, but most of the
release times were between 3 and 4 hours. Other HPMC grades were added to the
formulations both to make the composition easier to process and to alter the release profile.
Eventually, a combination of E15, K100M and DBS generated a release profile around 6
hours and earned an impact rating of 3.
As mentioned in the introduction section, one of the common methods for abuse is
to consume alcohol simultaneously with the dosage form to defeat the extended release
feature and attain dose dumping. Thus, the last step of the formulation process was to see
the release profile in 40% ethanol compared with the release in 0.1 N HCl to determine if
further formulation adjustments were needed. Figure 4.1 contains the dissolution profiles
of the two conditions for the lead formulation of 20% THEO / 35% HPMC E15 / 35%
HPMC K100M / 10% DBS.
105
Figure 4.1: Dissolution profiles of lead formulation in 0.1 N HCl and 40% Ethanol
(n=3).
The lead formulation actually had a slightly slower dissolution rate in the media
containing 40% ethanol than it did the standard media. An F2 similarity factor was
calculated to compare the two dissolution profiles and a value of 90 was obtained [189].
This indicated that there is less than 2% variance between the two profiles. Thus, the lead
formulation meets to the main performance criteria of releasing the drug over 6 hours,
having good mechanical properties for impact resistance, and having a release profile that
is not significantly altered by ethanol.
4.4.2 Abuse Testing
A reduction in particle size will cause an increase in the dissolution rate. Thus, one
of the abuse methods is to reduce the delivery form to a fine powder to have an immediate
0.0
20.0
40.0
60.0
80.0
100.0
0:00 1:30 3:00 4:30 6:00 7:30
% D
rug
Rel
ease
Time
0.1 N HCl Media
40% Ethanol Media
106
release rate. The multiparticulates produced in this study are in the size range of 1.7 to 4
mm. All the particles that were smaller than a 12 mesh screen were removed from the
multiparticulates, so the smallest size corresponds with the 12 mesh screen which is 1.7
mm. The 4 mm size on the large end of the spectrum corresponds with the milling screen
size. The coffee grinder size reduction test was conducted on the lead formulation with the
results of the mass fraction analysis shown in Figure 4.2.
Figure 4.2: Post Coffee Grinder Test Particle Size distribution.
The small sieve stack was limited in sizes, so the percentage of particles larger than
12 mesh could not be measured. However, almost 62% of the multiparticulates were over
the 20 mesh size which shows that very little size reduction did occur on the majority of
the particles. None of the particles were reduced in size to a fine powder (less than 75
microns) which is a positive result to keep the delivery form from being rendered an
immediate release. The remaining particles were scattered in sizes ranging from 75 to 850
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
<75 75-250 250-425 425-850 850+
0.0
12.5 14.810.9
61.8
Mas
s Fr
acti
on
(w
t%)
Particle Size (µm)
107
microns. The real indication of the effect of the coffee grinder size reduction test is to
perform a dissolution comparison which is illustrated in Figure 4.3.
Figure 4.3: Dissolution Profile of Original Size and Coffee Ground Material (n=3).
As expected, the ground material had a faster dissolution rate than the original size
material, but it was not an immediate release profile. The T95 (time where 95% of the
drug has been released) and T80 (time for 80%) was 4:42 and 2:32 for the original size and
3:32 and 1:42 for the coffee ground material, which is approximately a time reduction of
30%. An F2 similarity factor was calculated for the entire profile and for the first three
hours with values of 84 and 67 respectively, which is a difference of roughly 5%. While
it is a change in the dissolution performance, the ground material still retained an extended
release profile to serve as an abuse deterrent.
0.0
20.0
40.0
60.0
80.0
100.0
0:00 1:30 3:00 4:30 6:00 7:30
% D
rug
Rel
ease
Time
Original Size
Ground Material
108
Skeptics of this test might argue that the coffee grinder was only run intermittently
for 5 minutes and if it were processed consistently for a longer duration of time that the
particle size reduction would allow for immediate release. Prior to having access to a
Fitzmill in early KSD research studies, coffee grinders were used for size reduction of the
discharge of amorphous dispersions. Several coffee grinders were broken until a method
was discovered to grind high molecular weight polymers without causing damage to the
grinder. If the coffee grinders were run continuously, the surfaces of the particles are
heated up by the friction occurring in the grinder. As the surface temperatures of the
particles rises, they become soft and tacky. The tacky surfaces create a much higher
resistance to rotation, which will result in breaking the drive shaft or burning out the electric
motor. It is likely that an individual attempting to abuse the delivery form for the first time
would not take such precautions and cause damage to the coffee grinder, which would
probably motivate the person to change to a different method of tampering.
A mortar and pestle was employed to see if size reduction could be achieved.
Figure 4.4 is a picture of the material after test to show that no particle size reduction or
powder was formed.
Figure 4.4: Mortar and Pestle approach for size reduction of multiparticulates.
109
After 5 minutes of vigorously attempting size reduction in the mortar and pestle, no
size reduction was observed. A hammer test was briefly attempted, where the
multiparticulates were placed in a polyethylene bag and hit with a hammer. The first
impact did substantial damage to the plastic bag and the second impact caused some
multiparticulates to fly across the room. No size reduction was observed and the test was
ceased for safety reasons. With the results from the coffee grinder, mortar and pestle, and
hammer testing, it was concluded that the lead formulation did provide good resistance to
size reduction.
The syringeability test was then conducted on the lead formulation as illustrated in
Figure 4.5.
Figure 4.5: Result of Syringeability test of lead formulation.
As the particles were heated up, the surfaces in contact with the pan would melt
and then instantly char. Some of the particles in the figure demonstrate this as the bottom
is black while the top is still unmelted. It is possible that the heat transfer rate is too high
from the propane torch and causing the surface to burn before the top portion of the particle
110
received enough heat to melt. Consequently, the test was conducted on a hot plate where
the temperature was slowly raised over approximately 15 minutes to allow time for
sufficient heat transfer. Even with the slower heat transfer rate, the particles burned on the
bottom and remained solid on the top (picture not shown). Thus, this action was not a
result of the method of heating, but rather the performance of the formulation.
As the bottom of the particles started to melt/char, the pan was tilted to get the
material to flow the lip of the pan for possible collection in the needle. Interestingly, the
particles would move, but the portion that melted on the bottom would not flow. The
particle would slowly disintegrate as it slid along the pan, which would leave a trail, but
would stop moving once the particle completely melted. A trail can be seen in the picture
on the left hand side. The right hand side of the picture shows the portion of particles
completely melted together. After the particles on the right were melted, the pan was
slopped so that the material would flow to the right; however, the material would not pour.
As the pan was removed from the heat source, the liquefied portions became hard within a
few seconds. Because of the behavior of the material, none of it was able to be drawn
through the needle into the syringe. It was concluded that abuse by this method is not
practical.
The final step for testing abuse deterrence in this study was the water extraction
test. The results are shown in Figure 4.6.
111
Figure 4.6: Dissolution Profiles from the Water Extraction Test.
The delivery form did release slowly in ice water and room temperature water; at
the 1:15 time point there was 5% and 13% released respectively. However, the boiling
water allowed for around 40% of the drug to be released in the first 15 minutes.
Intriguingly, the multiparticulates in the boiling water appeared to have little or no physical
change as they were similar in hardness and color at the end of the test. The
multiparticulates placed in the room temperature and ice water baths had increased in size
due to water absorption, turned white in color and had taken a gelatin consistency. It seems
hydration of the formulation is key in retarding drug release and that hot water prevents
water absorption. This finding is consistent with product literature on HPMC [190, 191].
It is beyond the scope of this study to reformulate in an attempt to address the hot
water release issue. Possibly, using a lower grade of HPMC, like E3, along with a different
plasticizer or combination of plasticizers would allow for the composition to hydrate in
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
100.0
0:00 0:15 0:30 0:45 1:00 1:15 1:30
% D
rug
Rel
ease
Time
Boiling Water
Room Temp Water
Ice Water
112
boiling water while retaining the mechanical properties of the lead formulation. Effort on
achieving a more narrow range of particle sizes would provide a more uniform release rate
and varying the average particle size could modify the time to full drug release. Many
aspects could be investigated and optimized to improve this basic concept. However, the
study has shown that high molecular weight polymers, especially HPMC, can be
formulated for mechanical resistance to abuse methods and provide extended drug release.
113
4.5 CONCLUSION
Abuse of prescription medication is a large social challenge facing the United States
today. Abuse deterrent formulations have been introduced into the market and have shown
to discourage abusers from using those medicaments nonmedically. Some patient
populations struggle with swallowing those formulations and would benefit from a
multiparticulate abuse delivery form. This study has shown that high molecular weight
polymers, primarily HPMC, can be combined with plasticizers to create a delivery form
that is resistant to size reduction by coffee grinder, mortar and pestle and hammering. The
same formulation shows ethanol will not cause dose dumping and also resistance to
syringeability. While good water extraction resistance was established, it could be
improved upon to resist extraction in hot water. Further research could allow this concept
to be developed commercially and aid in the fight against the epidemic of prescription drug
overdose deaths.
114
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134
Vita
Chris Eugene Brough graduated from high school at Hong Kong International
School in 1991. After which he attended Brigham Young University in Provo, Utah. He
received B.S. and M.S. degrees in mechanical engineering and also completed a Master’s
degree in Business Administration from the Marriott School of Management. Upon
completing his education, he formed a company called ReSyk to exploit the technology he
developed in his master’s thesis.
ReSyk sold machines, called compounders, to companies that were looking to
recycle plastic directly into commodity products. ReSyk had 7 licensees of the technology
within the United States and Mexico when it sold to IntegriCo Composites in 2005.
IntegriCo moved to Temple, Texas, in 2006 to set up a large manufacturing facility to
produce plastic railroad ties from recycled post-industrial and post-consumer plastic. At
this time, Chris came into contact with Dave Miller, who was a Ph.D. student at the
University of Texas. Dave was trying to produce viscous, pharmaceutical amorphous
dispersions via hot melt extrusion with limited success. Chris and Dave tested a few of
these compositions in the large industrial compounders and had immediate success.
With this result, IntegriCo decided to form a spin-off company, called DisperSol
Technologies, to develop the technology for the pharmaceutical fields. Chris built a small,
lab scale compounder and placed it at the University in 2008 and worked with Ph.D.
candidates on the technology. At DisperSol’s persistent request, Chris became a student
in 2011 to explore new areas with the technology.
Email address: [email protected]
This dissertation was typed by the author.
